1 5532 183 RODENT MODELS OF GROUP 1 PULMONARY HYPERTENSION. WORLD HEALTH ORGANIZATION CATEGORY 1 PULMONARY HYPERTENSION (PH) IS A HETEROGENEOUS SYNDROME IN WHICH PH ORIGINATES IN THE SMALL PULMONARY ARTERIES AND IS THEREFORE ALSO REFERRED TO AS PULMONARY ARTERIAL HYPERTENSION (PAH). COMMON PATHOPHYSIOLOGIC FEATURES INCLUDE ENDOTHELIAL DYSFUNCTION, EXCESSIVE PROLIFERATION AND IMPAIRED APOPTOSIS OF VASCULAR CELLS, AND MITOCHONDRIAL FRAGMENTATION. THE PROLIFERATION/APOPTOSIS IMBALANCE RELATES IN PART TO ACTIVATION OF THE TRANSCRIPTION FACTORS HYPOXIA-INDUCIBLE FACTOR-1ALPHA (HIF-1ALPHA) AND NUCLEAR FACTOR OF ACTIVATED T-CELLS (NFAT) AND APOPTOSIS REPRESSORS, SUCH AS SURVIVIN. PERIVASCULAR INFLAMMATION, DISRUPTION OF ADVENTITIAL CONNECTIVE TISSUE, AND A GLYCOLYTIC METABOLIC SHIFT IN VASCULAR CELLS AND RIGHT VENTRICULAR MYOCYTES ALSO OCCUR IN PAH. THERE ARE IMPORTANT GENETIC AND EPIGENETIC PREDISPOSITIONS TO PAH. THIS REVIEW ASSESSES THE FIDELITY OF EXISTING ANIMAL MODELS TO HUMAN PAH. NO SINGLE MODEL CAN PERFECTLY RECAPITULATE THE MANY DIVERSE FORMS OF PH IN CATEGORY 1; HOWEVER, ACCEPTABLE MODELS EXIST. PAH INDUCED BY MONOCROTALINE AND CHRONIC HYPOXIA PLUS SU-5416 (CH+SU) IN RATS DISPLAY ENDOTHELIAL DYSFUNCTION, PROLIFERATION/APOPTOSIS IMBALANCE, AND DEVELOP THE GLYCOLYTIC METABOLIC PROFILE OF HUMAN PAH. HISTOLOGICALLY, CH+SU BEST CONFORMS TO PAH IN THAT IT DEVELOPS COMPLEX VASCULAR LESIONS, INCLUDING PLEXIFORM LESIONS. HOWEVER, THE MONOCROTALINE MODEL CAN BE INDUCED TO MANIFEST COMPLEX VASCULAR LESIONS AND DOES MANIFEST THE TENDENCY OF PAH PATIENTS TO DIE OF RIGHT VENTRICULAR (RV) FAILURE. MURINE MODELS OFFER GREATER MOLECULAR CERTAINTY THAN RAT MODELS BUT RARELY DEVELOP SIGNIFICANT PH, HAVE LESS RIGHT VENTRICULAR HYPERTROPHY (RVH) AND PULMONARY ARTERY (PA) REMODELING, AND ARE HARDER TO IMAGE AND CATHETERIZE. THE USE OF HIGH FIDELITY CATHETERIZATION AND ADVANCED IMAGING (MICROPET-CT, HIGH FREQUENCY ECHOCARDIOGRAPHY, HIGH FIELD STRENGTH MRI) AND FUNCTIONAL TESTING (TREADMILL) PERMIT ACCURATE PHENOTYPING OF EXPERIMENTAL MODELS OF PAH. PRECLINICAL TRIAL DESIGN IS AN IMPORTANT ASPECT OF TESTING EXPERIMENTAL PAH THERAPIES. THE USE OF MULTIPLE COMPLEMENTARY MODELS WITH ADEQUATE SAMPLE SIZE AND TRIAL DURATION AND APPROPRIATE ENDPOINTS ARE REQUIRED FOR PRECLINICAL ASSESSMENT OF EXPERIMENTAL PAH THERAPIES. 2013 2 1862 36 EMERGENCE OF FIBROBLASTS WITH A PROINFLAMMATORY EPIGENETICALLY ALTERED PHENOTYPE IN SEVERE HYPOXIC PULMONARY HYPERTENSION. PERSISTENT ACCUMULATION OF MONOCYTES/MACROPHAGES IN THE PULMONARY ARTERY ADVENTITIAL/PERIVASCULAR AREAS OF ANIMALS AND HUMANS WITH PULMONARY HYPERTENSION HAS BEEN DOCUMENTED. THE CELLULAR MECHANISMS CONTRIBUTING TO CHRONIC INFLAMMATORY RESPONSES REMAIN UNCLEAR. WE HYPOTHESIZED THAT PERIVASCULAR INFLAMMATION IS PERPETUATED BY ACTIVATED ADVENTITIAL FIBROBLASTS, WHICH, THROUGH SUSTAINED PRODUCTION OF PROINFLAMMATORY CYTOKINES/CHEMOKINES AND ADHESION MOLECULES, INDUCE ACCUMULATION, RETENTION, AND ACTIVATION OF MONOCYTES/MACROPHAGES. WE FURTHER HYPOTHESIZED THAT THIS PROINFLAMMATORY PHENOTYPE IS THE RESULT OF THE ABNORMAL ACTIVITY OF HISTONE-MODIFYING ENZYMES, SPECIFICALLY, CLASS I HISTONE DEACETYLASES (HDACS). PULMONARY ADVENTITIAL FIBROBLASTS FROM CHRONICALLY HYPOXIC HYPERTENSIVE CALVES (TERMED PH-FIBS) EXPRESSED A CONSTITUTIVE AND PERSISTENT PROINFLAMMATORY PHENOTYPE DEFINED BY HIGH EXPRESSION OF IL-1BETA, IL-6, CCL2(MCP-1), CXCL12(SDF-1), CCL5(RANTES), CCR7, CXCR4, GM-CSF, CD40, CD40L, AND VCAM-1. THE PROINFLAMMATORY PHENOTYPE OF PH-FIBS WAS ASSOCIATED WITH EPIGENETIC ALTERATIONS AS DEMONSTRATED BY INCREASED ACTIVITY OF HDACS AND THE FINDINGS THAT CLASS I HDAC INHIBITORS MARKEDLY DECREASED CYTOKINE/CHEMOKINE MRNA EXPRESSION LEVELS IN THESE CELLS. PH-FIBS INDUCED INCREASED ADHESION OF THP-1 MONOCYTES AND PRODUCED SOLUBLE FACTORS THAT INDUCED INCREASED MIGRATION OF THP-1 AND MURINE BONE MARROW-DERIVED MACROPHAGES AS WELL AS ACTIVATED MONOCYTES/MACROPHAGES TO EXPRESS PROINFLAMMATORY CYTOKINES AND PROFIBROGENIC MEDIATORS (TIMP1 AND TYPE I COLLAGEN) AT THE TRANSCRIPTIONAL LEVEL. CLASS I HDAC INHIBITORS MARKEDLY REDUCED THE ABILITY OF PH-FIBS TO INDUCE MONOCYTE MIGRATION AND PROINFLAMMATORY ACTIVATION. THE EMERGENCE OF A DISTINCT ADVENTITIAL FIBROBLAST POPULATION WITH AN EPIGENETICALLY ALTERED PROINFLAMMATORY PHENOTYPE CAPABLE OF RECRUITING, RETAINING, AND ACTIVATING MONOCYTES/MACROPHAGES CHARACTERIZES PULMONARY HYPERTENSION-ASSOCIATED VASCULAR REMODELING AND THUS COULD CONTRIBUTE SIGNIFICANTLY TO CHRONIC INFLAMMATORY PROCESSES IN THE PULMONARY ARTERY WALL. 2011 3 6499 37 TRAINED IMMUNITY IN PERIVASCULAR ADIPOSE TISSUE OF ABDOMINAL AORTIC ANEURYSM-A NOVEL CONCEPT FOR A STILL ELUSIVE DISEASE. ABDOMINAL AORTIC ANEURYSM (AAA) IS A CHRONIC, LIFE-THREATENING VASCULAR DISEASE WHOSE ONLY THERAPEUTIC OPTION IS A SURGICAL REPAIR TO PREVENT VESSEL RUPTURE. THE LACK OF MEDICAL THERAPY RESULTS FROM AN INADEQUATE UNDERSTANDING OF THE ETIOPATHOGENESIS OF AAA. MANY STUDIES IN ANIMAL AND HUMAN MODELS INDICATE A 'SHORT-CIRCUITING' OF THE REGULATION OF THE INFLAMMATORY-IMMUNE RESPONSE AS A MAJOR PLAYER IN THE AAA CHRONIC PROCESS. IN THIS REGARD, PERIVASCULAR ADIPOSE TISSUE (PVAT) HAS RECEIVED INCREASING INTEREST BECAUSE ITS DYSFUNCTION AFFECTS LARGE ARTERIES PRIMARILY THROUGH IMMUNE CELL INFILTRATION. CONSISTENTLY, WE HAVE RECENTLY PRODUCED EVIDENCE THAT INNATE AND ADAPTIVE IMMUNE CELLS PRESENT IN THE PVAT OF AAAS CONTRIBUTE TO SUSTAINING A DAMAGING INFLAMMATORY LOOP. HOWEVER, IT IS STILL UNCLEAR HOW THE COMPLEX CROSSTALK BETWEEN ADAPTIVE AND INNATE IMMUNITY CAN BE SELF-SUSTAINING. FROM OUR PERSPECTIVE, TRAINED IMMUNITY MAY PLAY A ROLE IN THIS CROSSTALK. TRAINED IMMUNITY IS DEFINED AS A FORM OF INNATE IMMUNE MEMORY RESULTING IN ENHANCED RESPONSIVENESS TO REPEATED TRIGGERS. SPECIFIC INNATE STIMULI AND EPIGENETIC AND METABOLIC REPROGRAMMING EVENTS INDUCE AND SHAPE TRAINED IMMUNITY IN MYELOID PROGENITOR CELLS IMPROVING HOST DEFENSE, BUT ALSO CONTRIBUTING TO THE PROGRESSION OF IMMUNE-MEDIATED AND CHRONIC INFLAMMATORY DISEASES. HERE WE PRESENT THIS HYPOTHESIS WITH DATA FROM THE LITERATURE AND OUR OBSERVATIONS TO SUPPORT IT. 2022 4 3121 38 GESTATIONAL INTERMITTENT HYPOXIA INDUCES ENDOTHELIAL DYSFUNCTION, REDUCES PERIVASCULAR ADIPONECTIN AND CAUSES EPIGENETIC CHANGES IN ADULT MALE OFFSPRING. KEY POINTS: OBSTRUCTIVE SLEEP APNOEA (OSA) IS CHARACTERIZED BY INTERMITTENT HYPOXIA, WHICH CAUSES OXIDATIVE STRESS AND INFLAMMATION AND INCREASES THE RISK OF CARDIOVASCULAR DISEASE. OSA DURING PREGNANCY CAUSES ADVERSE MATERNAL AND FETAL OUTCOMES. THE EFFECTS OF PRE-EXISTING OSA IN PREGNANT WOMEN ON CARDIOMETABOLIC OUTCOMES IN THE OFFSPRING ARE UNKNOWN. WE EVALUATED BASIC METABOLIC PARAMETERS, AS WELL AS AORTIC VASCULAR AND PERIVASCULAR ADIPOSE TISSUE (PVAT) FUNCTION IN RESPONSE TO ADIPONECTIN, AND EXAMINED DNA METHYLATION OF ADIPONECTIN GENE PROMOTER IN PVAT IN 16-WEEK-OLD ADULT OFFSPRING EXPOSED TO GESTATIONAL INTERMITTENT HYPOXIA (GIH). GIH DECREASED BODY WEIGHTS AT WEEK 1 IN BOTH MALE AND FEMALE OFFSPRING, AND CAUSED SUBSEQUENT INCREASES IN BODY WEIGHT AND FOOD CONSUMPTION IN MALE OFFSPRING ONLY. ADULT FEMALE OFFSPRING HAD NORMAL LEVELS OF LIPIDS, GLUCOSE AND INSULIN, WITH NO ENDOTHELIAL DYSFUNCTION. ADULT MALE OFFSPRING EXHIBITED DYSLIPIDAEMIA, INSULIN RESISTANCE AND HYPERLEPTINAEMIA. DECREASED ENDOTHELIAL-DEPENDENT VASODILATATION, LOSS OF ANTI-CONTRACTILE ACTIVITY OF PVAT AND LOW CIRCULATING PVAT ADIPONECTIN LEVELS, AS WELL AS INCREASED PRO-INFLAMMATORY GENE EXPRESSION AND DNA METHYLATION OF ADIPONECTIN GENE PROMOTER, OCCURRED IN ADULT MALE OFFSPRING. OUR RESULTS SUGGEST THAT MALE OFFSPRING OF WOMEN WITH OSA COULD BE AT RISK OF DEVELOPING CARDIOMETABOLIC DISEASE DURING ADULTHOOD. ABSTRACT: PERTURBATIONS DURING PREGNANCY CAN PROGRAM THE OFFSPRING TO DEVELOP CARDIOMETABOLIC DISEASES LATER IN LIFE. OBSTRUCTIVE SLEEP APNOEA (OSA) IS A CHRONIC CONDITION THAT FREQUENTLY AFFECTS PREGNANCIES AND LEADS TO ADVERSE FETAL OUTCOMES. WE ASSESSED THE OFFSPRING OF FEMALE MICE EXPERIENCING GESTATIONAL INTERMITTENT HYPOXIA (GIH), A HALLMARK OF OSA, FOR CHANGES IN METABOLIC PROFILES, AORTIC NITRIC OXIDE (NO)-DEPENDENT RELAXATIONS, PERIVASCULAR ADIPOSE TISSUE (PVAT) ANTI-CONTRACTILE ACTIVITIES AND THE RESPONSES TO ADIPONECTIN, AND DNA METHYLATION OF THE ADIPONECTIN GENE PROMOTER IN PVAT TISSUE. PREGNANT MOUSE DAMS WERE EXPOSED TO INTERMITTENT HYPOXIC CYCLES ( FIO2 21-12%) FOR 18 DAYS. GIH RESULTED IN LOWER BODY WEIGHTS OF PUPS AT WEEK 1, FOLLOWED BY SIGNIFICANT WEIGHT GAIN BY WEEK 16 OF AGE IN MALE BUT NOT FEMALE OFFSPRING. PLASMA LIPIDS, LEPTIN AND INSULIN RESISTANCE WERE HIGHER IN GIH MALE ADULT OFFSPRING. ENDOTHELIUM-DEPENDENT RELAXATION IN RESPONSE TO ACH AND THE ANTI-CONTRACTILE ACTIVITY OF PVAT IN THE ABDOMINAL AORTA WAS REDUCED IN GIH ADULT MALE OFFSPRING. INCUBATION OF ARTERIES FROM GIH ADULT MALE OFFSPRING WITH ADIPONECTIN RESTORED THE ANTI-CONTRACTILE ACTIVITY OF PVAT. BOTH CIRCULATING AND PVAT TISSUE HOMOGENATE LEVELS OF ADIPONECTIN, AS WELL AS GENE EXPRESSION OF ADIPONECTIN IN PVAT, WERE LOWER IN GIH MALE OFFSPRING, ALONG WITH AN INCREASED GENE EXPRESSION OF INFLAMMATORY CYTOKINES. PYROSEQUENCING OF ADIPONECTIN GENE PROMOTER IN PVAT SHOWED INCREASED DNA METHYLATION IN GIH MALE OFFSPRING. OUR RESULTS INDICATE THAT GIH LEADS TO VASCULAR DISEASE IN ADULT MALE OFFSPRING THROUGH PVAT DYSFUNCTION, WHICH WAS ASSOCIATED WITH LOW ADIPONECTIN LEVELS AND EPIGENETIC MODIFICATIONS ON THE ADIPONECTIN GENE PROMOTER. 2019 5 2278 41 EPIGENETIC REGULATION BY SUV4-20H1 IN CARDIOPULMONARY PROGENITOR CELLS IS REQUIRED TO PREVENT PULMONARY HYPERTENSION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. BACKGROUND: THE PATHOGENESIS OF LIFE-THREATENING CARDIOPULMONARY DISEASES SUCH AS PULMONARY HYPERTENSION (PH) AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ORIGINATES FROM A COMPLEX INTERPLAY OF ENVIRONMENTAL FACTORS AND GENETIC PREDISPOSITIONS THAT IS NOT FULLY UNDERSTOOD. LIKEWISE, LITTLE IS KNOWN ABOUT DEVELOPMENTAL ABNORMALITIES OR EPIGENETIC DYSREGULATIONS THAT MIGHT PREDISPOSE FOR PH OR COPD IN ADULT INDIVIDUALS. METHODS: TO IDENTIFY PATHOLOGY-ASSOCIATED EPIGENETIC ALTERATION IN DISEASED LUNG TISSUES, WE SCREENED A COHORT OF HUMAN PATIENTS WITH PH AND COPD FOR CHANGES OF HISTONE MODIFICATIONS BY IMMUNOFLUORESCENCE STAINING. TO ANALYZE THE FUNCTION OF H4K20ME2/3 IN LUNG PATHOGENESIS, WE DEVELOPED A SERIES OF SUV4-20H1 KNOCKOUT MOUSE LINES TARGETING CARDIOPULMONARY PROGENITOR CELLS AND DIFFERENT HEART AND LUNG CELL TYPES, FOLLOWED BY HEMODYNAMIC STUDIES AND MORPHOMETRIC ASSESSMENT OF TISSUE SAMPLES. MOLECULAR, CELLULAR, AND BIOCHEMICAL TECHNIQUES WERE APPLIED TO ANALYZE THE FUNCTION OF SUV4-20H1-DEPENDENT EPIGENETIC PROCESSES IN CARDIOPULMONARY PROGENITOR CELLS AND THEIR DERIVATIVES. RESULTS: WE DISCOVERED A STRONG REDUCTION OF THE HISTONE MODIFICATIONS OF H4K20ME2/3 IN HUMAN PATIENTS WITH COPD BUT NOT PATIENTS WITH PH THAT DEPEND ON THE ACTIVITY OF THE H4K20 DI-METHYLTRANSFERASE SUV4-20H1. LOSS OF SUV4-20H1 IN CARDIOPULMONARY PROGENITOR CELLS CAUSED A COPD-LIKE/PH PHENOTYPE IN MICE INCLUDING THE FORMATION OF PERIVASCULAR TERTIARY LYMPHOID TISSUE AND GOBLET CELL HYPERPLASIA, HYPERPROLIFERATION OF SMOOTH MUSCLE CELLS/MYOFIBROBLASTS, IMPAIRED ALVEOLARIZATION AND MATURATION DEFECTS OF THE MICROVASCULATURE LEADING TO MASSIVE RIGHT VENTRICULAR DILATATION AND PREMATURE DEATH. MECHANISTICALLY, SUV4-20H1 BINDS DIRECTLY TO THE 5'-UPSTREAM REGULATORY ELEMENT OF THE SUPEROXIDE DISMUTASE 3 (SOD3) GENE TO REPRESS ITS EXPRESSION. INCREASED LEVELS OF THE EXTRACELLULAR SOD3 ENZYME IN SUV4-20H1 MUTANTS INCREASES HYDROGEN PEROXIDE CONCENTRATIONS, CAUSING VASCULAR DEFECTS AND IMPAIRING ALVEOLARIZATION. CONCLUSIONS: OUR FINDINGS REVEAL A PIVOTAL ROLE OF THE HISTONE MODIFIER SUV4-20H1 IN CARDIOPULMONARY CODEVELOPMENT AND UNCOVER THE DEVELOPMENTAL ORIGINS OF CARDIOPULMONARY DISEASES. WE ASSUME THAT THE STUDY WILL FACILITATE THE UNDERSTANDING OF PATHOGENIC EVENTS CAUSING PH AND COPD AND AID THE DEVELOPMENT OF EPIGENETIC DRUGS FOR THE TREATMENT OF CARDIOPULMONARY DISEASES. 2021 6 4109 35 MECHANISMS AND DRUG THERAPY OF PULMONARY HYPERTENSION AT HIGH ALTITUDE. PULMONARY VASOCONSTRICTION REPRESENTS A PHYSIOLOGICAL ADAPTIVE MECHANISM TO HIGH ALTITUDE. IF EXAGGERATED, HOWEVER, IT IS ASSOCIATED WITH IMPORTANT MORBIDITY AND MORTALITY. RECENT MECHANISTIC STUDIES USING SHORT-TERM ACUTE HIGH ALTITUDE EXPOSURE HAVE PROVIDED INSIGHT INTO THE IMPORTANCE OF DEFECTIVE VASCULAR ENDOTHELIAL AND RESPIRATORY EPITHELIAL NITRIC OXIDE (NO) SYNTHESIS, INCREASED ENDOTHELIN-1 BIOAVAILABILITY, AND OVERACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM IN CAUSING EXAGGERATED HYPOXIC PULMONARY HYPERTENSION IN HUMANS. BASED ON THESE STUDIES, DRUGS THAT INCREASE NO BIOAVAILABILITY, ATTENUATE ENDOTHELIN-1 INDUCED PULMONARY VASOCONSTRICTION, OR PREVENT EXAGGERATED SYMPATHETIC ACTIVATION HAVE BEEN SHOWN TO BE USEFUL FOR THE TREATMENT/PREVENTION OF EXAGGERATED PULMONARY HYPERTENSION DURING ACUTE SHORT-TERM HIGH ALTITUDE EXPOSURE. THE MECHANISMS UNDERPINNING CHRONIC PULMONARY HYPERTENSION IN HIGH ALTITUDE DWELLERS ARE LESS WELL UNDERSTOOD, BUT RECENT EVIDENCE SUGGESTS THAT THEY DIFFER IN SOME ASPECTS FROM THOSE INVOLVED IN SHORT-TERM ADAPTATION TO HIGH ALTITUDE. THESE DIFFERENCES HAVE CONSEQUENCES FOR THE CHOICE OF THE TREATMENT FOR CHRONIC PULMONARY HYPERTENSION AT HIGH ALTITUDE. FINALLY, RECENT DATA INDICATE THAT FETAL PROGRAMMING OF PULMONARY VASCULAR DYSFUNCTION IN OFFSPRING OF PREECLAMPSIA AND CHILDREN GENERATED BY ASSISTED REPRODUCTIVE TECHNOLOGIES REPRESENTS A NOVEL AND FREQUENT CAUSE OF PULMONARY HYPERTENSION AT HIGH ALTITUDE. IN ANIMAL MODELS OF FETAL PROGRAMMING OF HYPOXIC PULMONARY HYPERTENSION, EPIGENETIC MECHANISMS PLAY A ROLE, AND TARGETING OF THESE MECHANISMS WITH DRUGS LOWERS PULMONARY ARTERY PRESSURE. IF EPIGENETIC MECHANISMS ALSO ARE OPERATIONAL IN THE FETAL PROGRAMMING OF PULMONARY VASCULAR DYSFUNCTION IN HUMANS, SUCH DRUGS MAY BECOME NOVEL TOOLS FOR THE TREATMENT OF HYPOXIC PULMONARY HYPERTENSION. 2013 7 2356 48 EPIGENETIC REGULATION OF PULMONARY ARTERIAL HYPERTENSION-INDUCED VASCULAR AND RIGHT VENTRICULAR REMODELING: NEW OPPORTUNITIES? PULMONARY ARTERY HYPERTENSION (PAH) IS A RARE CHRONIC DISEASE WITH HIGH IMPACT ON PATIENTS' QUALITY OF LIFE AND CURRENTLY NO AVAILABLE CURE. PAH IS CHARACTERIZED BY CONSTANT REMODELING OF THE PULMONARY ARTERY BY INCREASED PROLIFERATION AND MIGRATION OF PULMONARY ARTERIAL SMOOTH MUSCLE CELLS (PASMCS), FIBROBLASTS (FBS) AND ENDOTHELIAL CELLS (ECS). THIS REMODELING EVENTUALLY LEADS TO INCREASED PRESSURE IN THE RIGHT VENTRICLE (RV) AND SUBSEQUENT RIGHT VENTRICLE HYPERTROPHY (RVH) WHICH, WHEN LEFT UNTREATED, PROGRESSES INTO RIGHT VENTRICLE FAILURE (RVF). PAH CAN NOT ONLY ORIGINATE FROM HERITABLE MUTATIONS, BUT ALSO DEVELOP AS A CONSEQUENCE OF CONGENITAL HEART DISEASE, EXPOSURE TO DRUGS OR TOXINS, HIV, CONNECTIVE TISSUE DISEASE OR BE IDIOPATHIC. WHILE MUCH ATTENTION WAS DRAWN INTO INVESTIGATING AND DEVELOPING THERAPIES RELATED TO THE MOST WELL UNDERSTOOD SIGNALING PATHWAYS IN PAH, IN THE LAST DECADE, A SHIFT TOWARDS UNDERSTANDING THE EPIGENETIC MECHANISMS DRIVING THE DISEASE OCCURRED. IN THIS REVIEW, WE REFLECT ON THE DIFFERENT EPIGENETIC REGULATORY FACTORS THAT ARE ASSOCIATED WITH THE PATHOLOGY OF RV REMODELING, AND ON THEIR RELEVANCE TOWARDS A BETTER UNDERSTANDING OF THE DISEASE AND SUBSEQUENTLY, THE DEVELOPMENT OF NEW AND MORE EFFICIENT THERAPEUTIC STRATEGIES. 2020 8 3846 36 IS ATHEROSCLEROSIS A NEUROGENIC PHENOMENON? IDENTIFIED RISK FACTORS FOR ATHEROSCLEROSIS INCLUDE DIET, AGE, GENDER, FAMILY HISTORY, STRESS, LIFESTYLE, SMOKING, DIABETES, DYSLIPIDEMIAS, HYPERTENSION, AND HIV. THE MECHANISTIC RATIONALE TO EXPLAIN THESE ASSOCIATIONS REMAINS POORLY UNDERSTOOD. WE BELIEVE THAT THESE SEEMINGLY UNRELATED ENTITIES MAY PROMOTE ATHEROSCLEROSIS THROUGH A COMMON PATHWAY BY INDUCING ADVENTITIAL AUTONOMIC DYSFUNCTION, SPECIFICALLY AS AN ADVENTITIAL STRESS DYSFUNCTION OF NEUROGENIC ORIGIN. ATHEROSCLEROSIS MAY REPRESENT A LOCAL VASCULAR MANIFESTATION OF THE GLOBAL AUTONOMIC DYSFUNCTION INDUCED BY AGE, SMOKING, HYPERTENSION, HIV, AND DIABETES. ATHEROSCLEROSIS MAY ALSO PARTICIPATE IN A FEED-FORWARD CYCLE AS AGING, DIABETES, DYSLIPIDEMIA, AND HYPERTENSION MAY ALSO REPRESENT INDEPENDENT DOWNSTREAM CONSEQUENCES OF GLOBAL SYMPATHETIC BIAS. CHRONIC PHYSIOLOGIC STRESS AND BEHAVIORAL STRESS CAN SHIFT THE AUTONOMIC BALANCE TOWARDS A STATE OF SYMPATHETIC PREDOMINANCE. THE HIGHLY COMMUNICABLE NATURE OF BEHAVIORAL STRESS MAY PARTIALLY IMPLICATE THE FAMILIAL ASSOCIATION OF ATHEROSCLEROSIS AS AN EPIGENETIC PHENOMENON, INDEPENDENT OF PUTATIVE GENETIC MECHANISMS. HOST STRESS, GLOBAL AUTONOMIC DYSFUNCTION, AND SYMPATHETIC BIAS MAY ALSO ARISE FROM CHRONIC MALADAPTIVE CONSUMPTION OF STRESSED FOODS, AS ORGANISMS DETECT AND ASSIMILATE THE STRESS PHENOTYPES OF THEIR DIETARY CONSTITUENTS THROUGH A PROCESS CALLED XENOHORMESIS. THE BENEFITS OF EXERCISE MAY OPERATE THROUGH REDUCTION OF CHRONIC PHYSIOLOGIC STRESS ASSOCIATED WITH GLOBAL SYMPATHETIC BIAS. THE NEUROGENIC ADVENTITIAL STRESS RESPONSE MAY EXPLAIN THE LOCAL TISSUE REMODELING SEEN IN ATHEROSCLEROSIS, INCLUDING ADVENTITIAL ADIPOSE DYSFUNCTION, INFLAMMATION, ADVENTITIAL ANGIOGENESIS, THROMBOSIS, AND ENDOTHELIAL DYSFUNCTION. WE BELIEVE THAT THE LOCATIONS OF ATHEROSCLEROTIC LESIONS CORRESPOND TO REGIONS OF NEUROGENIC ADVENTITIAL AUTONOMIC DYSFUNCTION, IN SIMILAR FASHION TO THE SEGMENTAL PATTERNS OF INVOLVEMENT FOUND IN INFLAMMATORY BOWEL DISEASE. THE DIFFUSE ATHEROSCLEROSIS EXHIBITED IN TRANSPLANTED HEARTS MAY REFLECT A DIFFUSE SYMPATHETIC BIAS OF THE DONOR HEART, SINCE TISSUES AND ORGANS EXHIBIT AN INTRINSIC SYMPATHETIC BIAS IN THE ABSENCE OF AN EXTRINSIC SOURCE OF AUTONOMIC HEGEMONY. ONCE WE REGARD ATHEROSCLEROSIS AS A NEUROGENIC PHENOMENON MANIFESTED IN ADVENTITIAL AUTONOMIC DYSFUNCTION, NOVEL DIAGNOSTIC AND THERAPEUTIC PARADIGMS BECOME EVIDENT. 2007 9 4138 36 MECHANISMS OF MICROGLIAL ACTIVATION IN MODELS OF INFLAMMATION AND HYPOXIA: IMPLICATIONS FOR CHRONIC INTERMITTENT HYPOXIA. CHRONIC INTERMITTENT HYPOXIA (CIH) IS A HALLMARK OF SLEEP APNOEA, A CONDITION ASSOCIATED WITH DIVERSE CLINICAL DISORDERS. CIH AND SLEEP APNOEA ARE CHARACTERIZED BY INCREASED REACTIVE OXYGEN SPECIES FORMATION, PERIPHERAL AND CNS INFLAMMATION, NEURONAL DEATH AND NEUROCOGNITIVE DEFICITS. FEW STUDIES HAVE EXAMINED THE ROLE OF MICROGLIA, THE RESIDENT CNS IMMUNE CELLS, IN MODELS OF CIH. THUS, LITTLE IS KNOWN CONCERNING THEIR DIRECT CONTRIBUTIONS TO NEUROPATHOLOGY OR THE CELLULAR MECHANISMS REGULATING THEIR ACTIVITIES DURING OR FOLLOWING PATHOLOGICAL CIH. IN THIS REVIEW, WE IDENTIFY GAPS IN KNOWLEDGE REGARDING CIH-INDUCED MICROGLIAL ACTIVATION, AND PROPOSE MECHANISMS BASED ON DATA FROM RELATED MODELS OF HYPOXIA AND/OR HYPOXIA-REOXYGENATION. CIH MAY DIRECTLY AFFECT MICROGLIA, OR MAY HAVE INDIRECT EFFECTS VIA THE PERIPHERY OR OTHER CNS CELLS. PERIPHERAL INFLAMMATION MAY INDIRECTLY ACTIVATE MICROGLIA VIA ENTRY OF PRO-INFLAMMATORY MOLECULES INTO THE CNS, AND/OR ACTIVATION OF VAGAL AFFERENTS THAT TRIGGER CNS INFLAMMATION. CIH-INDUCED RELEASE OF DAMAGE-ASSOCIATED MOLECULAR PATTERNS FROM INJURED CNS CELLS MAY ALSO ACTIVATE MICROGLIA VIA INTERACTIONS WITH PATTERN RECOGNITION RECEPTORS EXPRESSED ON MICROGLIA. FOR EXAMPLE, TOLL-LIKE RECEPTORS ACTIVATE MITOGEN-ACTIVATED PROTEIN KINASE/TRANSCRIPTION FACTOR PATHWAYS REQUIRED FOR MICROGLIAL INFLAMMATORY GENE EXPRESSION. ALTHOUGH EPIGENETIC EFFECTS FROM CIH HAVE NOT YET BEEN STUDIED IN MICROGLIA, POTENTIAL EPIGENETIC MECHANISMS IN MICROGLIAL REGULATION ARE DISCUSSED, INCLUDING MICRORNAS, HISTONE MODIFICATIONS AND DNA METHYLATION. EPIGENETIC EFFECTS CAN OCCUR DURING CIH, OR LONG AFTER IT HAS ENDED. A BETTER UNDERSTANDING OF CIH EFFECTS ON MICROGLIAL ACTIVITIES MAY BE IMPORTANT TO REVERSE CIH-INDUCED NEUROPATHOLOGY IN PATIENTS WITH SLEEP DISORDERED BREATHING. 2016 10 5084 36 PIGMENTED EPENDYMOMA, A TUMOR WITH PREDILECTION FOR THE MIDDLE-AGED ADULT: CASE REPORT WITH METHYLATION CLASSIFICATION AND REVIEW OF 16 LITERATURE CASES. EPENDYMOMAS HAVE RARELY BEEN DESCRIBED TO CONTAIN PIGMENT OTHER THAN MELANIN, NEUROMELANIN, LIPOFUSCIN OR A COMBINATION. IN THIS CASE REPORT, WE PRESENT A PIGMENTED EPENDYMOMA IN THE FOURTH VENTRICLE OF AN ADULT PATIENT AND REVIEW 16 ADDITIONAL CASES OF PIGMENTED EPENDYMOMA FROM THE LITERATURE. A 46-YEAR-OLD FEMALE SHOWED UP WITH HEARING LOSS, HEADACHES, AND NAUSEA. MAGNETIC RESONANCE IMAGING REVEALED A 2.5 CM CONTRAST-ENHANCING CYSTIC MASS IN THE FOURTH VENTRICLE, WHICH WAS RESECTED. INTRAOPERATIVELY, THE TUMOR APPEARED GREY-BROWN, CYSTIC, AND WAS ADHERENT TO THE BRAINSTEM. ROUTINE HISTOLOGY REVEALED A TUMOR WITH TRUE ROSETTES, PERIVASCULAR PSEUDOROSETTES AND EPENDYMAL CANALS CONSISTENT WITH EPENDYMOMA, BUT ALSO SHOWED CHRONIC INFLAMMATION AND ABUNDANT DISTENDED PIGMENTED TUMOR CELLS THAT MIMICKED MACROPHAGES IN FROZEN AND PERMANENT SECTIONS. THE PIGMENTED CELLS WERE POSITIVE FOR GFAP AND NEGATIVE FOR CD163 CONSONANT WITH GLIAL TUMOR CELLS. THE PIGMENT WAS NEGATIVE FOR FONTANA-MASSON, POSITIVE FOR PERIODIC-ACID SCHIFF AND AUTOFLUORESCENT, WHICH COINCIDE WITH CHARACTERISTICS OF LIPOFUSCIN. PROLIFERATION INDICES WERE LOW AND H3K27ME3 SHOWED PARTIAL LOSS. H3K27ME 3 IS AN EPIGENETIC MODIFICATION TO THE DNA PACKAGING PROTEIN HISTONE H3 THAT INDICATES THE TRI-METHYLATION OF LYSINE 27 ON HISTONE H3 PROTEIN. THIS METHYLATION CLASSIFICATION WAS COMPATIBLE WITH A POSTERIOR FOSSA GROUP B EPENDYMOMA (EPN_PFB). THE PATIENT WAS CLINICALLY WELL WITHOUT RECURRENCE AT THREE-MONTH POST-OPERATIVE FOLLOW-UP APPOINTMENT. OUR ANALYSIS OF ALL 17 CASES, INCLUDING THE ONE PRESENTED, SHOWS THAT PIGMENTED EPENDYMOMAS ARE MOST COMMON IN THE MIDDLE-AGED WITH A MEDIAN AGE OF 42 YEARS AND MOST HAVE A FAVORABLE OUTCOME. HOWEVER, ONE PATIENT THAT ALSO DEVELOPED SECONDARY LEPTOMENINGEAL MELANIN ACCUMULATIONS DIED. MOST (58.8%) ARISE IN THE 4TH VENTRICLE, WHILE SPINAL CORD (17.6%) AND SUPRATENTORIAL LOCATIONS (17.6%) WERE LESS COMMON. THE AGE OF PRESENTATION AND GENERALLY GOOD PROGNOSIS RAISE THE QUESTION OF WHETHER MOST OTHER POSTERIOR FOSSA PIGMENTED EPENDYMOMAS MAY ALSO FALL INTO THE EPN_PFB GROUP, BUT ADDITIONAL STUDY IS REQUIRED TO ADDRESS THAT QUESTION. 2022 11 3120 31 GESTATIONAL HYPOXIA AND BLOOD-BRAIN BARRIER PERMEABILITY: EARLY ORIGINS OF CEREBROVASCULAR DYSFUNCTION INDUCED BY EPIGENETIC MECHANISMS. FETAL CHRONIC HYPOXIA LEADS TO INTRAUTERINE GROWTH RESTRICTION (IUGR), WHICH IS LIKELY TO REDUCE OXYGEN DELIVERY TO THE BRAIN AND INDUCE LONG-TERM NEUROLOGICAL IMPAIRMENTS. THESE INDICATE A MODULATORY ROLE FOR OXYGEN IN CEREBROVASCULAR DEVELOPMENT. DURING INTRAUTERINE HYPOXIA, THE FETAL CIRCULATION SUFFERS MARKED ADAPTATIONS IN THE FETAL CARDIAC OUTPUT TO MAINTAIN OXYGEN AND NUTRIENT DELIVERY TO VITAL ORGANS, KNOWN AS THE "BRAIN-SPARING PHENOTYPE." THIS IS A WELL-CHARACTERIZED RESPONSE; HOWEVER, LITTLE IS KNOWN ABOUT THE POSTNATAL COURSE AND OUTCOMES OF THIS FETAL CEREBROVASCULAR ADAPTATION. IN ADDITION, SEVERAL NEURODEVELOPMENTAL DISORDERS HAVE THEIR ORIGINS DURING GESTATION. STILL, FEW STUDIES HAVE FOCUSED ON HOW INTRAUTERINE FETAL HYPOXIA MODULATES THE NORMAL BRAIN DEVELOPMENT OF THE BLOOD-BRAIN BARRIER (BBB) IN THE IUGR NEONATE. THE BBB IS A CELLULAR STRUCTURE FORMED BY THE NEUROVASCULAR UNIT (NVU) AND IS ORGANIZED BY A MONOLAYER OF ENDOTHELIAL AND MURAL CELLS. THE BBB REGULATES THE ENTRY OF PLASMA CELLS AND MOLECULES FROM THE SYSTEMIC CIRCULATION TO THE BRAIN. A HIGHLY SELECTIVE PERMEABILITY SYSTEM ACHIEVES THIS THROUGH INTEGRAL MEMBRANE PROTEINS IN BRAIN ENDOTHELIAL CELLS. BBB BREAKDOWN AND DYSFUNCTION IN CEREBROVASCULAR DISEASES LEAD TO LEAKAGE OF BLOOD COMPONENTS INTO THE BRAIN PARENCHYMA, CONTRIBUTING TO NEUROLOGICAL DEFICITS. THE FETAL BRAIN CIRCULATION IS PARTICULARLY SUSCEPTIBLE IN IUGR AND IS PROPOSED TO BE ONE OF THE MAIN PATHOLOGICAL PROCESSES DERIVING BBB DISRUPTION. IN THE LAST DECADE, SEVERAL EPIGENETIC MECHANISMS ACTIVATED BY IU HYPOXIA HAVE BEEN PROPOSED TO REGULATE THE POSTNATAL BBB PERMEABILITY. HOWEVER, FEW MECHANISTIC STUDIES ABOUT THIS TOPIC ARE AVAILABLE, AND LITTLE EVIDENCE SHOWS CONTROVERSY. THEREFORE, IN THIS MINI-REVIEW, WE ANALYZE THE BBB PERMEABILITY-ASSOCIATED EPIGENETIC MECHANISMS IN THE BRAIN EXPOSED TO CHRONIC INTRAUTERINE HYPOXIA. 2021 12 5048 42 PHARMACOLOGICAL APPROACHES IN EITHER INTERMITTENT OR PERMANENT HYPOXIA: A TALE OF TWO EXPOSURES. HYPOXIA INDUCES SEVERAL RESPONSES AT CARDIOVASCULAR, PULMONARY AND REPRODUCTIVE LEVELS, WHICH MAY LEAD TO CHRONIC DISEASES. THIS IS RELEVANT IN HUMAN POPULATIONS EXPOSED TO HIGH ALTITUDE (HA), IN EITHER CHRONIC CONTINUOUS (PERMANENT INHABITANTS) OR INTERMITTENT FASHION (HA WORKERS, TOURISTS AND MOUNTAINEERS). IN CHILE, IT IS ESTIMATED THAT 1.000.000 PEOPLE LIVE AT HIGHLANDS AND MORE THAN 55.000 WORK IN HA SHIFTS. INITIAL RESPONSES TO HYPOXIA ARE COMPENSATORY AND INDUCE ACTIVATION OF CARDIOPROTECTIVE MECHANISMS, SUCH AS THOSE SEEN UNDER INTERMITTENT HYPOBARIC (IH) HYPOXIA, EVENTS THAT COULD MEDIATE PRECONDITIONING. HOWEVER, WHENEVER HYPOXIA IS PROLONGED, THE CHRONIC ACTIVATION OF CELLULAR RESPONSES INDUCES LONG-LASTING MODIFICATIONS THAT MAY RESULT IN ACCLIMATIZATION OR PRODUCE MALADAPTIVE CHANGES WITH INCREASE IN CARDIOVASCULAR RISK. HA EXPOSURE DURING PREGNANCY INDUCES HYPOXIA AND OXIDATIVE STRESS, WHICH IN TURN MAY PROMOTE CELLULAR RESPONSES AND EPIGENETIC MODIFICATIONS RESULTING IN SEVERE IMPAIRMENT IN GROWTH AND DEVELOPMENT. SADLY, THIS CONDITION IS ACCOMPANIED WITH AN INCREASED FETAL AND NEONATAL MORBI-MORTALITY. FURTHER, DEVELOPMENTAL HYPOXIA MAY PROGRAM CARDIO-PULMONARY CIRCULATIONS LATER IN POSTNATAL LIFE, ENDING IN VASCULAR STRUCTURAL AND FUNCTIONAL ALTERATIONS WITH AUGMENTED RISK ON PULMONARY AND CARDIOVASCULAR FAILURE. ADDITIONALLY, PERMANENT HA INHABITANTS HAVE AUGMENTED RISK AND PREVALENCE OF CHRONIC HYPOXIC PULMONARY HYPERTENSION, RIGHT VENTRICULAR HYPERTROPHY AND CARDIOPULMONARY REMODELING. SIMILAR RESPONSES ARE SEEN IN ADULTS THAT ARE INTERMITTENTLY EXPOSED TO CHRONIC HYPOXIA (CH) SUCH AS SHIFT WORKERS IN HA AREAS. THE MECHANISMS INVOLVED DETERMINING THE IMMEDIATE, SHORT AND LONG-LASTING EFFECTS ARE STILL UNCLEAR. FOR SEVERAL YEARS, THE STUDY OF THE RESPONSES TO HYPOXIC INSULTS AND PHARMACOLOGICAL TARGETS HAS BEEN THE MOTIVATION OF OUR GROUP. THIS REVIEW DESCRIBES SOME OF THE MECHANISMS UNDERLYING HYPOXIC RESPONSES AND POTENTIAL THERAPEUTIC APPROACHES WITH ANTIOXIDANTS SUCH AS MELATONIN, ASCORBATE, OMEGA 3 (OMEGA3) OR COMPOUNDS THAT INCREASE THE NITRIC OXIDE (NO) BIOAVAILABILITY. 2015 13 4197 30 METABOLIC PROFILES IN OVINE CAROTID ARTERIES WITH DEVELOPMENTAL MATURATION AND LONG-TERM HYPOXIA. BACKGROUND: LONG-TERM HYPOXIA (LTH) IS AN IMPORTANT STRESSOR RELATED TO HEALTH AND DISEASE DURING DEVELOPMENT. AT DIFFERENT TIME POINTS FROM FETUS TO ADULT, WE ARE EXPOSED TO HYPOXIC STRESS BECAUSE OF PLACENTAL INSUFFICIENCY, HIGH-ALTITUDE RESIDENCE, SMOKING, CHRONIC ANEMIA, PULMONARY, AND HEART DISORDERS, AS WELL AS CANCERS. INTRAUTERINE HYPOXIA CAN LEAD TO FETAL GROWTH RESTRICTION AND LONG-TERM SEQUELAE SUCH AS COGNITIVE IMPAIRMENTS, HYPERTENSION, CARDIOVASCULAR DISORDERS, DIABETES, AND SCHIZOPHRENIA. SIMILARLY, PROLONGED HYPOXIC EXPOSURE DURING ADULT LIFE CAN LEAD TO ACUTE MOUNTAIN SICKNESS, CHRONIC FATIGUE, CHRONIC HEADACHE, COGNITIVE IMPAIRMENT, ACUTE CEREBRAL AND/OR PULMONARY EDEMA, AND DEATH. AIM: LTH ALSO CAN LEAD TO ALTERATION IN METABOLITES SUCH AS FUMARATE, 2-OXOGLUTARATE, MALATE, AND LACTATE, WHICH ARE LINKED TO EPIGENETIC REGULATION OF GENE EXPRESSION. IMPORTANTLY, DURING THE INTRAUTERINE LIFE, A FETUS IS UNDER A RELATIVE HYPOXIC ENVIRONMENT, AS COMPARED TO NEWBORN OR ADULT. THUS, THE CHANGES IN GENE EXPRESSION WITH DEVELOPMENT FROM FETUS TO NEWBORN TO ADULT MAY BE AS A CONSEQUENCE OF UNDERLYING CHANGES IN THE METABOLIC PROFILE BECAUSE OF THE HYPOXIC ENVIRONMENT ALONG WITH DEVELOPMENTAL MATURATION. TO EXAMINE THIS POSSIBILITY, WE EXAMINED THE METABOLIC PROFILE IN CAROTID ARTERIES FROM NEAR-TERM FETUS, NEWBORN, AND ADULT SHEEP IN BOTH NORMOXIC AND LONG-TERM HYPOXIC ACCLIMATIZED GROUPS. RESULTS: OUR RESULTS DEMONSTRATE THAT LTH DIFFERENTIALLY REGULATED GLUCOSE METABOLISM, MITOCHONDRIAL METABOLISM, NICOTINAMIDE COFACTOR METABOLISM, OXIDATIVE STRESS AND ANTIOXIDANTS, MEMBRANE LIPID HYDROLYSIS, AND FREE FATTY ACID METABOLISM, EACH OF WHICH MAY PLAY A ROLE IN GENETIC-EPIGENETIC REGULATION. 2015 14 3975 41 LONG-TERM CONSEQUENCES OF PLACENTAL VASCULAR PATHOLOGY ON THE MATERNAL AND OFFSPRING CARDIOVASCULAR SYSTEMS. OVER THE LAST THIRTY YEARS, EVIDENCE HAS BEEN ACCUMULATING THAT HYPERTENSIVE DISORDERS OF PREGNANCY (HDP) AND, SPECIFICALLY, PREECLAMPSIA (PE) PRODUCE NOT ONLY LONG-TERM EFFECTS ON THE PREGNANT WOMAN, BUT HAVE ALSO LASTING CONSEQUENCES FOR THE FETUS. AT THE CORE OF THESE CONSEQUENCES IS THE PHENOMENON KNOWN AS DEFECTIVE DEEP PLACENTATION, BEING PRESENT IN VIRTUALLY EVERY MAJOR OBSTETRICAL SYNDROME. THE PROFOUND PLACENTAL VASCULAR LESIONS CHARACTERISTIC OF THIS PATHOLOGY CAN INDUCE LONG-TERM ADVERSE CONSEQUENCES FOR THE PREGNANT WOMAN'S ENTIRE ARTERIAL SYSTEM. IN ADDITION, PLACENTAL GROWTH RESTRICTION AND FUNCTION CAN, IN TURN, CAUSE A DECREASED BLOOD SUPPLY TO THE FETUS, WITH LONG-LASTING EFFECTS. WOMEN WITH A HISTORY OF HDP HAVE AN INCREASED RISK OF CARDIOVASCULAR DISEASES (CVD) COMPARED WITH WOMEN WITH NORMAL PREGNANCIES. SPECIFICALLY, THESE SUBJECTS ARE AT A FUTURE HIGHER RISK OF: HYPERTENSION; CORONARY ARTERY DISEASE; HEART FAILURE; PERIPHERAL VASCULAR DISEASE; CEREBROVASCULAR ACCIDENTS (STROKE); CVD-RELATED MORTALITY. VASCULAR PATHOLOGY IN PREGNANCY AND CVD MAY SHARE A COMMON ETIOLOGY AND MAY HAVE COMMON RISK FACTORS, WHICH ARE UNMASKED BY THE "STRESS" OF PREGNANCY. IT IS ALSO POSSIBLE THAT THE FUTURE OCCURRENCE OF A CVD MAY BE THE CONSEQUENCE OF ENDOTHELIAL DYSFUNCTION GENERATED BY PREGNANCY-INDUCED HYPERTENSION THAT PERSISTS AFTER DELIVERY. ALTHOUGH BIOCHEMICAL AND BIOPHYSICAL MARKERS OF PE ABOUND, INFORMATION ON MARKERS FOR A COMPARATIVE EVALUATION IN THE VARIOUS GROUPS IS STILL LACKING. LONG-TERM CONSEQUENCES FOR THE FETUS ARE AN INTEGRAL PART OF THE THEORY OF A FETAL ORIGIN OF A NUMBER OF ADULT DISEASES, KNOWN AS THE BARKER HYPOTHESIS. INDEED, INTRAUTERINE MALNUTRITION AND FETAL GROWTH RESTRICTION REPRESENT SIGNIFICANT RISK FACTORS FOR THE DEVELOPMENT OF CHRONIC HYPERTENSION, DIABETES, STROKE AND DEATH FROM CORONARY ARTERY DISEASE IN ADULTS. OTHER FACTORS WILL ALSO INFLUENCE THE DEVELOPMENT LATER IN LIFE OF HYPERTENSION, CORONARY AND MYOCARDIAL DISEASE; THEY INCLUDE PARENTAL GENETIC DISPOSITION, EPIGENETIC MODIFICATIONS, ENDOTHELIAL DYSFUNCTION, CONCURRENT INTRAUTERINE EXPOSURES, AND THE LIFESTYLE OF THE AFFECTED INDIVIDUAL. 2021 15 6150 37 THE FETAL CEREBRAL CIRCULATION: THREE DECADES OF EXPLORATION BY THE LLU CENTER FOR PERINATAL BIOLOGY. FOR MORE THAN THREE DECADES, RESEARCH PROGRAMS IN THE CENTER OF PERINATAL BIOLOGY HAVE FOCUSED ON THE VASCULAR BIOLOGY OF THE FETAL CEREBRAL CIRCULATION. IN THE 1980S, RESEARCH IN THE CENTER DEMONSTRATED THAT CEREBRAL AUTOREGULATION OPERATED OVER A NARROWER PRESSURE RANGE, AND WAS MORE VULNERABLE TO INSULTS, IN FETUSES THAN IN ADULTS. OTHER STUDIES WERE AMONG THE FIRST TO ESTABLISH THAT COMPARED TO ADULT CEREBRAL ARTERIES, FETAL CEREBRAL ARTERIES WERE MORE HYDRATED, CONTAINED SMALLER SMOOTH MUSCLE CELLS AND LESS CONNECTIVE TISSUE, AND HAD ENDOTHELIUM LESS CAPABLE OF PRODUCING NO. WORK IN THE 1990S REVEALED THAT PREGNANCY DEPRESSED REACTIVITY TO NO IN EXTRA-CEREBRAL ARTERIES, BUT ELEVATED IT IN CEREBRAL ARTERIES THROUGH EFFECTS INVOLVING CHANGES IN CGMP METABOLISM. COMPARATIVE STUDIES VERIFIED THAT FETAL LAMB CEREBRAL ARTERIES WERE AN EXCELLENT MODEL FOR CEREBRAL ARTERIES FROM HUMAN INFANTS. BIOCHEMICAL STUDIES DEMONSTRATED THAT CGMP METABOLISM WAS DRAMATICALLY UPREGULATED, BUT THAT CONTRACTION WAS FAR MORE DEPENDENT ON CALCIUM INFLUX, IN FETAL COMPARED TO ADULT CEREBRAL ARTERIES. FURTHER STUDIES ESTABLISHED THAT CHRONIC HYPOXIA ACCELERATES FUNCTIONAL MATURATION OF FETAL CEREBRAL ARTERIES, AS INDICATED BY INCREASED CONTRACTILE RESPONSES TO ADRENERGIC AGONISTS AND PERIVASCULAR ADRENERGIC NERVES. IN THE 2000S, STUDIES OF SIGNAL TRANSDUCTION ESTABLISHED AGE-DEPENDENT ROLES FOR PKG, PKC, PKA, ERK, ODC, IP3, MYOFILAMENT CALCIUM SENSITIVITY, AND MANY OTHER MECHANISMS. THESE DIVERSE STUDIES CLEARLY DEMONSTRATED THAT FETAL CEREBRAL ARTERIES WERE FUNCTIONALLY QUITE DISTINCT COMPARED TO ADULT CEREBRAL ARTERIES. IN THE CURRENT DECADE, RESEARCH IN THE CENTER HAS EXPANDED TO A MORE MOLECULAR FOCUS ON EPIGENETIC MECHANISMS AND THEIR ROLE IN FETAL VASCULAR ADAPTATION TO CHRONIC HYPOXIA, MATERNAL DRUG ABUSE, AND NUTRIENT DEPRIVATION. OVERALL, THE PAST THREE DECADES HAVE TRANSFORMED THINKING ABOUT, AND UNDERSTANDING OF, THE FETAL CEREBRAL CIRCULATION DUE IN NO SMALL PART TO THE SUSTAINED RESEARCH EFFORTS BY FACULTY AND STAFF IN THE CENTER FOR PERINATAL BIOLOGY. 2014 16 6742 38 WHITHER THE ETIOPATHOGENESIS (AND SCOLIOGENY) OF ADOLESCENT IDIOPATHIC SCOLIOSIS? ALTHOUGH CONSIDERABLE PROGRESS HAD BEEN MADE IN THE PAST TWO DECADES IN UNDERSTANDING THE ETIOPATHOGENESIS OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), IT STILL LACKS AN AGREED THEORY OF ETIOPATHOGENESIS. ONE PROBLEM MAY BE THAT AIS RESULTS NOT FROM ONE CAUSE, BUT SEVERAL THAT INTERACT WITH VARIOUS GENETIC PREDISPOSING FACTORS. THERE IS A VIEW THERE ARE TWO OTHER PATHOGENIC PROCESSES FOR IDIOPATHIC SCOLIOSIS NAMELY, INITIATING (OR INDUCING), AND THOSE THAT CAUSE CURVE PROGRESSION. TWIN STUDIES AND OBSERVATIONS OF FAMILY AGGREGATION HAVE REVEALED SIGNIFICANT GENETIC CONTRIBUTIONS TO IDIOPATHIC SCOLIOSIS, THAT PLACE AIS AMONG OTHER COMMON DISEASE OR COMPLEX TRAITS WITH A HIGH HERITABILITY INTERPRETED BY THE GENETIC VARIANT HYPOTHESIS OF DISEASE. WE SUMMARIZE ETIOPATHOGENETIC KNOWLEDGE OF AIS AS THEORIES OF PATHOGENESIS INCLUDING RECENT MULTIPLE CONCEPTS, AND BLOOD TESTS FOR AIS BASED ON PREDICTIVE BIOMARKERS AND GENETIC VARIANTS THAT SIGNIFY DISEASE RISK. THERE IS INCREASING EVIDENCE FOR THE POSSIBILITY OF AN UNDERLYING NEUROLOGICAL DISORDER FOR AIS, RESEARCH WHICH HOLDS PROMISE. LIKE BRAIN RESEARCH, MOST AIS WORKERS FOCUS ON THEIR OWN CORNER AND THERE IS A NEED FOR GREATER INTEGRATION OF RESEARCH EFFORT. EPIGENETICS, A RELATIVELY RECENT FIELD, EVALUATES FACTORS CONCERNED WITH GENE EXPRESSION IN RELATION TO ENVIRONMENT, DISEASE, NORMAL DEVELOPMENT AND AGING, WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. RESEARCH ON THE ROLE OF ENVIRONMENTAL FACTORS, EPIGENETICS AND CHRONIC NON-COMMUNICABLE DISEASES (NCDS) INCLUDING ADIPOSITY, AFTER A SLOW START, HAS EXPLODED IN THE LAST DECADE. NOT SO FOR AIS RESEARCH AND THE ENVIRONMENT WHERE, EXCEPT FOR MONOZYGOTIC TWIN STUDIES, THERE ARE ONLY SPORADIC REPORTS TO SUGGEST THAT ENVIRONMENTAL FACTORS ARE AT WORK IN ETIOLOGY. HERE, WE EXAMINE EPIGENETIC CONCEPTS AS THEY MAY RELATE TO HUMAN DEVELOPMENT, NORMAL LIFE HISTORY PHASES AND AIS PATHOGENESIS. ALTHOUGH AIS IS NOT REGARDED AS AN NCD, LIKE THEM, IT IS ASSOCIATED WITH WHOLE ORGANISM METABOLIC PHENOMENA, INCLUDING LOWER BODY MASS INDEX, LOWER CIRCULATING LEPTIN LEVELS AND OTHER SYSTEMIC DISORDERS. SOME EPIGENETIC RESEARCH APPLIED TO SILVER-RUSSELL SYNDROME AND ADIPOSITY IS EXAMINED, FROM WHICH SUGGESTIONS ARE MADE FOR CONSIDERATION OF AIS EPIGENETIC RESEARCH, CROSS-SECTIONAL AND LONGITUDINAL. THE WORD SCOLIOGENY IS SUGGESTED TO INCLUDE ETIOLOGY, PATHOGENESIS AND PATHOMECHANISM. 2012 17 5179 32 PREGNANCY: AN UNDERUTILIZED WINDOW OF OPPORTUNITY TO IMPROVE LONG-TERM MATERNAL AND INFANT HEALTH-AN APPEAL FOR CONTINUOUS FAMILY CARE AND INTERDISCIPLINARY COMMUNICATION. PHYSIOLOGIC ADAPTATIONS DURING PREGNANCY UNMASK A WOMAN'S PREDISPOSITION TO DISEASES. COMPLICATIONS ARE INCREASINGLY PREDICTED BY FIRST-TRIMESTER ALGORITHMS, AMPLIFY A PRE-EXISTING MATERNAL PHENOTYPE AND ACCELERATE RISKS FOR CHRONIC DISEASES IN THE OFFSPRING UP TO ADULTHOOD (BARKER HYPOTHESIS). RECENT EVIDENCE SUGGESTS THAT VICE VERSA, PREGNANCY DISEASES ALSO INDICATE MATERNAL AND EVEN GRANDPARENT'S RISKS FOR CHRONIC DISEASES (REVERSE BARKER HYPOTHESIS). PUB-MED AND EMBASE WERE REVIEWED FOR MESH TERMS "FETAL PROGRAMMING" AND "PREGNANCY COMPLICATIONS COMBINED WITH MATERNAL DISEASE" UNTIL JANUARY 2017. STUDIES LINKING PREGNANCY COMPLICATIONS TO FUTURE CARDIOVASCULAR, METABOLIC, AND THROMBOTIC RISKS FOR MOTHER AND OFFSPRING WERE REVIEWED. WOMEN WITH A HISTORY OF MISCARRIAGE, FETAL GROWTH RESTRICTION, PREECLAMPSIA, PRETERM DELIVERY, OBESITY, EXCESSIVE GESTATIONAL WEIGHT GAIN, GESTATIONAL DIABETES, SUBFERTILITY, AND THROMBOPHILIA MORE FREQUENTLY DEMONSTRATE WITH ECHOCARDIOGRAPHIC ABNORMALITIES, HIGHER FASTING INSULIN, DEVIATING LIPIDS OR CLOTTING FACTORS AND SHOW DEFECTIVE ENDOTHELIAL FUNCTION. THROMBOPHILIA HINTS TO THROMBOTIC RISKS IN LATER LIFE. PREGNANCY ABNORMALITIES CORRELATE WITH FUTURE CARDIOVASCULAR AND METABOLIC COMPLICATIONS AND EARLIER MORTALITY. CONVERSELY, WOMEN WITH A NORMAL PREGNANCY HAVE LOWER RATES OF SUBSEQUENT DISEASES THAN THE GENERAL FEMALE POPULATION CREATING THE TERM: "PREGNANCY AS A WINDOW FOR FUTURE HEALTH." ALTHOUGH THE PLACENTA WORKS AS A GATEKEEPER, MANY PREGNANCY COMPLICATIONS MAY LEAD TO SICKNESS AND EARLIER DEATH IN LATER LIFE WHEN THE CHILD BECOMES AN ADULT. THE EPIGENETIC MECHANISMS AND THE MISMATCH BETWEEN PRE- AND POSTNATAL LIFE HAVE CREATED THE TERM "FETAL ORIGIN OF ADULT DISEASE." UP TO NOW, THE IMPACT OF CARDIOVASCULAR, METABOLIC, OR THROMBOTIC RISK PROFILES HAS BEEN INVESTIGATED SEPARATELY FOR MOTHER AND CHILD. IN THIS MANUSCRIPT, WE STRIVE TO ILLUSTRATE THE CONSEQUENCES FOR BOTH, FETUS AND MOTHER WITHIN A COHESIVE PERSPECTIVE AND THUS TRY TO DEMONSTRATE THE COMPLEX INTERRELATIONSHIP OF GENETICS AND EPIGENETICS FOR LONG-TERM HEALTH OF SOCIETIES AND FUTURE GENERATIONS. MATERNAL-FETAL MEDICINE SPECIALISTS SHOULD HAVE A KEY ROLE IN THE PREVENTION OF NON-COMMUNICABLE DISEASES BY IMPLEMENTING A FRAMEWORK FOR PATIENT CONSULTATION AND INTERDISCIPLINARY NETWORKS. HEALTH-CARE PROVIDERS AND POLICY MAKERS SHOULD INCREASINGLY INVEST IN A STRATIFIED PRIMARY PREVENTION AND FOLLOW-UP TO REDUCE THE INCREASING NUMBER OF MANIFEST CARDIOVASCULAR AND METABOLIC DISEASES AND TO PREVENT WASTE OF HEALTH-CARE RESOURCES. 2017 18 1177 36 CONTROL OF BREATHING AND THE CIRCULATION IN HIGH-ALTITUDE MAMMALS AND BIRDS. HYPOXIA IS AN UNREMITTING STRESSOR AT HIGH ALTITUDES THAT PLACES A PREMIUM ON OXYGEN TRANSPORT BY THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS. PHENOTYPIC PLASTICITY AND GENOTYPIC ADAPTATION AT VARIOUS STEPS IN THE O2 CASCADE COULD HELP OFFSET THE EFFECTS OF HYPOXIA ON CELLULAR O2 SUPPLY IN HIGH-ALTITUDE NATIVES. IN THIS REVIEW, WE WILL DISCUSS THE UNIQUE MECHANISMS BY WHICH VENTILATION, CARDIAC OUTPUT, AND BLOOD FLOW ARE CONTROLLED IN HIGH-ALTITUDE MAMMALS AND BIRDS. ACCLIMATIZATION TO HIGH ALTITUDES LEADS TO SOME CHANGES IN RESPIRATORY AND CARDIOVASCULAR CONTROL THAT INCREASE O2 TRANSPORT IN HYPOXIA (E.G., VENTILATORY ACCLIMATIZATION TO HYPOXIA). HOWEVER, ACCLIMATIZATION OR DEVELOPMENT IN HYPOXIA CAN ALSO MODIFY CARDIORESPIRATORY CONTROL IN WAYS THAT ARE MALADAPTIVE FOR O2 TRANSPORT. HYPOXIA RESPONSES THAT AROSE AS SHORT-TERM SOLUTIONS TO O2 DEPRIVATION (E.G., PERIPHERAL VASOCONSTRICTION) OR REGIONAL VARIATION IN O2 LEVELS IN THE LUNGS (I.E., HYPOXIC PULMONARY VASOCONSTRICTION) ARE DETRIMENTAL AT IN CHRONIC HIGH-ALTITUDE HYPOXIA. EVOLVED CHANGES IN CARDIORESPIRATORY CONTROL HAVE ARISEN IN MANY HIGH-ALTITUDE TAXA, INCLUDING INCREASES IN EFFECTIVE VENTILATION, ATTENUATION OF HYPOXIC PULMONARY VASOCONSTRICTION, AND CHANGES IN CATECHOLAMINE SENSITIVITY OF THE HEART AND SYSTEMIC VASCULATURE. PARALLEL EVOLUTION OF SOME OF THESE CHANGES IN INDEPENDENT HIGHLAND LINEAGES SUPPORTS THEIR ADAPTIVE SIGNIFICANCE. MUCH LESS IS KNOWN ABOUT THE GENOMIC BASES AND POTENTIAL INTERACTIVE EFFECTS OF ADAPTATION, ACCLIMATIZATION, DEVELOPMENTAL PLASTICITY, AND TRANS-GENERATIONAL EPIGENETIC TRANSFER ON CARDIORESPIRATORY CONTROL. FUTURE WORK TO UNDERSTAND THESE VARIOUS INFLUENCES ON BREATHING AND CIRCULATION IN HIGH-ALTITUDE NATIVES WILL HELP ELUCIDATE HOW COMPLEX PHYSIOLOGICAL SYSTEMS CAN BE PUSHED TO THEIR LIMITS TO MAINTAIN CELLULAR FUNCTION IN HYPOXIA. 2015 19 107 45 A REVIEW OF PRE-CLINICAL MODELS FOR GULF WAR ILLNESS. GULF WAR ILLNESS (GWI) IS A CHRONIC MULTISYMPTOMATIC DISORDER THAT AFFLICTS OVER 1/3RD OF THE 1991 GW VETERANS. IT SPANS MULTIPLE BODILY SYSTEMS AND PRESENTS ITSELF AS A SYNDROME EXHIBITING DIVERSE SYMPTOMS INCLUDING FATIGUE, DEPRESSION, MOOD, AND MEMORY AND CONCENTRATION DEFICITS, MUSCULOSKELETAL PAIN AND GASTROINTESTINAL DISTRESS IN GW VETERANS. THE ETIOLOGY OF GWI IS COMPLEX AND MANY FACTORS, INCLUDING CHEMICAL, PHYSIOLOGICAL, AND ENVIRONMENTAL STRESSORS PRESENT IN THE GW ARENA, HAVE BEEN IMPLICATED FOR ITS DEVELOPMENT. IT HAS BEEN OVER 30 YEARS SINCE THE END OF THE GW BUT, GWI HAS BEEN PERSISTENT IN SUFFERING VETERANS WHO ARE ALSO DEALING WITH PAUCITY OF EFFECTIVE TREATMENTS. THE MULTIFACTORIAL ASPECT OF GWI ALONG WITH GENETIC HETEROGENEITY AND LACK OF AVAILABLE DATA SURROUNDING WAR-TIME EXPOSURES HAVE PROVED TO BE CHALLENGING IN DEVELOPING PRE-CLINICAL MODELS OF GWI. DESPITE THIS, OVER A DOZEN GWI ANIMAL MODELS EXIST IN THE LITERATURE. IN THIS ARTICLE, FOLLOWING A BRIEF DISCUSSION OF GW HISTORY, GWI DEFINITIONS, AND PROBABLE CAUSES FOR ITS PATHOGENESIS, WE WILL EXPAND UPON VARIOUS EXPERIMENTAL MODELS USED IN GWI LABORATORY RESEARCH. THESE ANIMAL MODELS WILL BE DISCUSSED IN THE CONTEXT OF THEIR ATTEMPTS AT MIMICKING GW-RELATED EXPOSURES WITH REGARDS TO THE VARIATIONS IN CHEMICAL COMBINATIONS, DOSES, AND FREQUENCY OF EXPOSURES. WE WILL DISCUSS THEIR ADVANTAGES AND LIMITATIONS IN MODELING GWI FOLLOWED BY A DISCUSSION OF BEHAVIORAL AND MOLECULAR FINDINGS IN THESE MODELS. THE MECHANISTIC DATA OBTAINED FROM THESE PRECLINICAL STUDIES HAVE OFFERED MULTIPLE MOLECULAR PATHWAYS INCLUDING CHRONIC INFLAMMATION, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, LIPID DISTURBANCES, CALCIUM HOMEOSTATIC ALTERATIONS, CHANGES IN GUT MICROBIOTA, AND EPIGENETIC MODIFICATIONS, AMONGST OTHERS FOR EXPLAINING GWI DEVELOPMENT AND ITS PERSISTENCE. FINALLY, THESE FINDINGS HAVE ALSO INFORMED US ON NOVEL DRUGGABLE TARGETS IN GWI. WHILE, IT HAS BEEN DIFFICULT TO CONCEIVE A SINGLE PRE-CLINICAL MODEL THAT COULD EXPRESS ALL THE GWI SIGNS AND EXHIBIT BIOLOGICAL COMPLEXITY REFLECTIVE OF THE CLINICAL PRESENTATION IN GWI, ANIMAL MODELS HAVE BEEN CRITICAL FOR IDENTIFYING MOLECULAR UNDERPINNINGS OF GWI AND EVALUATING TREATMENT STRATEGIES FOR GWI. 2021 20 2511 36 EPIGENETICS AND PREECLAMPSIA: PROGRAMMING OF FUTURE OUTCOMES. PREGNANCY IS KNOWN TO INDUCE RAPID, PROGRESSIVE, AND SUBSTANTIAL CHANGES TO THE CARDIOVASCULAR SYSTEM, ULTIMATELY FACILITATING SUCCESSFUL PREGNANCY OUTCOMES. WOMEN WHO DEVELOP HYPERTENSIVE DISORDERS DURING PREGNANCY ARE CONSIDERED TO HAVE "FAILED" THE CARDIOVASCULAR STRESS TEST OF PREGNANCY AND LIKELY REPRESENT A SUBPOPULATION WITH INADEQUATE CARDIOVASCULAR ACCOMMODATION. PREECLAMPSIA IS A SERIOUS COMPLICATION WITH A MYRIAD OF MANIFESTATIONS IN BOTH MOTHER AND OFFSPRING. THIS PREGNANCY SYNDROME IS A POLYGENIC DISEASE AND HAS NOW BEEN LINKED TO A GREATER INCIDENCE OF CARDIOVASCULAR DISEASE. MOREOVER, OFFSPRINGS BORN TO PREECLAMPTIC MOTHERS EXHIBIT AN ELEVATED RISK OF CARDIOVASCULAR DISEASE, STROKE, AND MENTAL DISORDERS DURING ADULTHOOD. THIS SUGGESTS THAT PREECLAMPSIA NOT ONLY EXPOSES THE MOTHER AND THE FETUS TO COMPLICATIONS DURING PREGNANCY BUT ALSO PROGRAMS CHRONIC DISEASES DURING ADULTHOOD IN THE OFFSPRING. THE ETIOLOGY OF PREECLAMPSIA REMAINS UNKNOWN, WITH VARIOUS THEORIES BEING SUGGESTED TO EXPLAIN ITS ORIGIN. IT IS PRIMARILY THOUGHT TO BE ASSOCIATED WITH POOR PLACENTATION AND ENTAILS EXCESSIVE MATERNAL INFLAMMATION AND ENDOTHELIAL DYSFUNCTION. IT IS WELL ESTABLISHED NOW THAT THE MATERNAL IMMUNE SYSTEM AND THE PLACENTA ARE INVOLVED IN A HIGHLY CHOREOGRAPHED CROSS TALK THAT UNDERLIES ADEQUATE SPIRAL ARTERY REMODELING REQUIRED FOR UTEROPLACENTAL PERFUSION AND FREE FLOW OF NUTRIENTS TO THE FETUS. ALTHOUGH IT IS NOT CLEAR WHETHER IMMUNOLOGICAL ALTERATIONS OCCUR EARLY DURING PREGNANCY, STUDIES HAVE PROPOSED THAT DYSREGULATED SYSTEMIC AND PLACENTAL IMMUNITY CONTRIBUTE TO IMPAIRED ANGIOGENESIS AND THE ONSET OF PREECLAMPSIA. RECENTLY EMERGED STRONG EVIDENCE SUGGESTS A POTENTIAL LINK AMONG EPIGENETICS, MICRORNAS (MIRNAS), AND PREGNANCY COMPLICATIONS. THIS CHAPTER WILL FOCUS ON IMPORTANT ASPECTS OF EPIGENETICS, IMMUNOLOGICAL ASPECTS, AND CARDIOVASCULAR AND VASCULAR REMODELING OF PREECLAMPSIA. 2018