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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL073895-01A2
Application #
6919759
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Barouch, Winifred
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
1
Fiscal Year
2005
Total Cost
$342,000
Indirect Cost
Name
University of Vermont & St Agric College
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Osol, George; Barron, Carolyn; MandalĂ , Maurizio (2012) Uterine distension differentially affects remodelling and distensibility of the uterine vasculature in non-pregnant rats. Reprod Fertil Dev 24:835-42
Mandala, Maurizio; Osol, George (2012) Physiological remodelling of the maternal uterine circulation during pregnancy. Basic Clin Pharmacol Toxicol 110:12-8
Hale, Sarah A; Weger, Lindsey; Mandala, Maurizio et al. (2011) Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition. Am J Physiol Heart Circ Physiol 301:H1266-75
Fuller, Robert; Colton, Ilsley; Gokina, Natalia et al. (2011) Local versus systemic influences on uterine vascular reactivity during pregnancy in the single-horn gravid rat. Reprod Sci 18:723-9
Barron, Carolyn; Mandala, Maurizio; Osol, George (2010) Effects of pregnancy, hypertension and nitric oxide inhibition on rat uterine artery myogenic reactivity. J Vasc Res 47:463-71
Hale, Sarah A; Jones, Cresta W; Osol, George et al. (2010) Sildenafil increases uterine blood flow in nonpregnant nulliparous women. Reprod Sci 17:358-65
Wedel Jones, Cresta; Mandala, Maurizio; Barron, Carolyn et al. (2009) Mechanisms underlying maternal venous adaptation in pregnancy. Reprod Sci 16:596-604
Osol, George; Barron, Carolyn; Gokina, Natalia et al. (2009) Inhibition of nitric oxide synthases abrogates pregnancy-induced uterine vascular expansive remodeling. J Vasc Res 46:478-86
Gokina, Natalia I; Kuzina, Olga Y; Fuller, Robert et al. (2009) Local uteroplacental influences are responsible for the induction of uterine artery myogenic tone during rat pregnancy. Reprod Sci 16:1072-81
Burger, Natalie Z; Kuzina, Olga Y; Osol, George et al. (2009) Estrogen replacement enhances EDHF-mediated vasodilation of mesenteric and uterine resistance arteries: role of endothelial cell Ca2+. Am J Physiol Endocrinol Metab 296:E503-12

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