MATURATION OF CEREBROVASCULAR RELAXANT MECHANISMS

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Cardiovascular homeostasis is delicately balanced between contractile and relaxant influences in all vascular beds. Among relaxant mechanisms, some of the most important are related to the vascular endothelium and its ability to release vasoactive factors. Although the functional importance of the vascular endothelium is widely accepted, the mechanisms whereby endothelial function changes during postnatal maturation have not been widely studied and remain poorly understood, despite growing evidence that endothelial function varies dramatically between immature and mature vascular beds. Because immature endothelial function in the cerebrovascular bed could potentially contribute to the pronounced morbidity and mortality associated with even mild cerebrovascular insults in neonates, the present studies address the general hypothesis that postnatal maturation selectively enhances endothelium-dependent cerebral vasodilatation in an artery-specific manner. This main hypothesis has two corollaries, each of which proposes a mechanism whereby endothelial function is altered: 1) endothelial cell eNOS activity is enhanced; or 2) vascular guanylate cyclase activity is enhanced. To evaluate these ideas, we will conduct experiments designed to determine: 1) the morphological relations between endothelial and vascular smooth muscle cells; 2) the capacity for endothelium-mediated vasodilatation in whole arteries in the presence and absence of cyclooxygenase, eNOS, and soluble guanylate cyclase inhibitors; 3) the capacity and kinetics of endothelial nitric oxide production in both intact and homogenized artery preparations; 4) the abundances of eNOS protein and mRNA using Western blotting and quantitative RT-PCR; 5) vascular soluble guanylate cyclase synthetic capacity and kinetics in both intact and homogenized artery preparations; and 6) the abundances of vascular soluble guanylate cyclase protein and mRNA using Western blotting and quantitative RT-PCR. To address the effects of perinatal maturation on cerebrovascular endothelial function, we will conduct these experiments in both newborn lambs and non-pregnant adults. To define the importance of arterial size and type, all experiments will be conducted in a series of arteries including the common carotid, basilar, posterior communicating, and middle cerebral arteries. Together, the results of these experiments will enable an unprecedented assessment of the cellular mechanisms whereby maturation modulates cerebrovascular endothelial function.