The regulation of blood flow to the brain is of great importance, particularly during fetal/neonatal development. Dysfunction of this regulation, as not uncommonly occurs in the fetus and premature newborn, can result in vessel rupture with intraventricular hemorrhage and neurological sequelae. In the US alone, over 10,000 such brain damaged infants are born each year. As compared to the adult, cerebral arteries of the fetus demonstrate major differences in response to adrenergic and other agonists. As we have reported, many elements of both calcium-dependent and calcium-independent signaling pathways are poorly developed in the immature organism. Thus, an understanding of the signal transduction mechanisms of cerebral vessels, and how these change with development is critical. The overall hypothesis of these studies is that the alteration of cerebrovascular reactivity during development is secondary to changes in the biochemical pharmaco-mechanical and electro-mechanical signal transduction mechanisms of both Ca2+- dependent and Ca2+-independent pathways. In cerebral arteries of the fetus and adult, we will test four specific hypotheses for which we have evidence, as follows. 1) Maturational changes result, in part, from differences in the lineage of protein kinase C (PKC) to specific enzymes in the MAPK/ERK cascade and their downstream effectors. 2) Developmental changes in adrenergic-mediated responses result from differences in the alpha1-adrenergic receptor (alpha1-AR) subtypes and their second messengers. 3) Developmental responses result from differences in the role of Rho A/Rho kinase activity, and interactions with downstream effectors. 4) Age-related changes also result from differences in the activity of plasma membrane K channels, which determine membrane potential, and therefore vascular tone, their regulation by protein kinases, and their regulation of Ca2+ channel activity. To address maturational effects, we will perform studies in fetal (0.95 gestation) and nonpregnant sheep (and in selected instances in 0.75 gestation and newborns). These studies are innovative, and will provide new and important insights into the basic mechanisms of the regulation of cerebral vascular reactivity in the adult. Of particular importance, the studies also will contribute to an understanding of these mechanisms during the course of maturation from fetus to adult, and to the mechanistic basis of their immaturity. Of clinical relevance, they will contribute to understanding the pathophysiology of problems associated with dysregulation of cerebral blood flow in the fetus/newborn including intracerebral hemorrhage and various neurological sequelae (cerebral palsy, seizure disorders mental retardation, minimal brain dysfunction, and related problems). Overall, these studies will form a basis for gene or other therapy for the prevention and/or amelioration of these disorders.
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