Project Summary. The overall theme of this project is to understand at a deeper level the epigenetic-mediated signal transduction mechanisms by which the cerebrovasculature in the fetus and adult become acclimatized to high altitude, long-term hypoxia (LTH). This project is broadly based and vertically integrated using physiological, cellular, biochemical, and molecular approaches by four investigators trained in multiple disciplines and methodologies. Based on over two and one-half decades of intense investigation of the regulation of cerebrovascular reactivity, we shall test the hypothesis that acclimatization to long-term hypoxia is mediated, importantly and in part by epigenetic-mediated alpha1-adrenergic receptor (α1-AR) subtypes (α1A, α1B, - α1D), and their individual and unique roles in gene transcription. Our Specific Aims involve testing several associated hypotheses regarding both long-term hypoxia and developmental maturation including that of: What is the role of DNA methylation on transcription of alpha1-AR subtypes? What is the role of histone modifications (acetylation, methylation, and others) in α1-AR subtype-mediated transcription? What is the role of hypoxic-mediated microRNAs in this regard? What is the role of sympathetic innervation and α1-AR subtype in cerebral blood flow (CBF) regulation? What is the role of DNA methylation, histone acetylation, histone methylation, microRNA-mediated regulation of α1-AR subtype in CBF regulation as a consequence of LTH.?Scientifically the studies will augment our understanding of basic mechanisms whereby fetal and adult cerebral vessels acclimatize to LTH. They also will illustrate aspects of developmental regulation from fetus to adult. Clinically the studies relate to at least three critical problems. 1) For the fetus and newborn they relate to responses to prolonged hypoxia as occurs in women who live at high altitude, as well as those who smoke or are anemic, who have heart or lung disease; for the newborn altered cerebrovascular blood flow with intracerebral hemorrhage and pulmonary hypertension. 2) They also will contribute to understanding the epigenetic-mediated mechanisms of cardiovascular disorders and prenatal “programming” of adult disease. This includes the role of sympathetic innervation in this regard. 3) In addition, they are relevant to understanding epigenetic-mediated mechanisms of diseases such as: Acute Mountain Sickness, Preeclampsia, and High Altitude Cerebral and Pulmonary Edema.