Hypertension during pregnancy is a leading cause of maternal morbidity and mortality worldwide, accounting for up to 10% of pregnancy-related deaths. Although elevated peripheral resistance is the hallmark of hypertension, surprisingly few studies have examined the effects of hypertension during pregnancy on resistance artery structural and functional adaptation that is essential for normal pregnancy outcome. In this project, the unifying hypothesis is that maternal hypertension abrogates the normal process of resistance artery gestational adaptation through specific and identifiable cellular mechanisms that govern vessel reactivity and structure. The use of an established model of gestational hypertension (nitric oxide inhibition), along with several co-treatment protocols, will allow us to distinguish and define the consequences of elevated transmural pressure per se vs. loss of NO paracrine signaling on gestational changes in uterine and mesenteric artery remodeling (Aim 1), biomechanical properties (Aim 2), contractility (Aim 3) and VSM phenotypic expression (Aim 4). From a mechanistic standpoint, we are particularly interested in understanding the impact of hypertension/NO loss on matrix metalloproteinase activity and elastin content, two critical determinants of vascular remodeling and compliance, and on the RhoA and PKC signalling pathways that are important determinants of calcium sensitivity and small artery reactivity. The proposed studies are structured around eight working hypotheses and are designed within the framework of regional adaptation, as uterine and mesenteric arteries differ substantially in their physiological function, and in their patterns of adaptation to gestational influences. The significance of this project lies in its potential for generating new insights into the mechanisms by which elevated transmural pressure and/or reduced nitric oxide signaling influences vascular smooth muscle structure, function and phenotypic adaptation during pregnancy.
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