During pregnancy, a profound increase in uterine blood flow occurs via a complex and integrated process of vascular enlargement and altered reactivity. VEGF (Vascular Endothelial Growth Factor) and PlGF (Placental Growth Factor) are pleiotropic growth factors whose vascular actions are mediated by two dominant receptor subtypes: VEGFR-1 and VEGFR-2. PlGF is produced and secreted by the placenta and, unlike VEGF, binds specifically to the VEGFR-1 receptor. The PlGF-VEGFR-1 story is exciting in view of recent findings that reveal its ability to stimulate vessel enlargement and vasodilation, and to modulate the actions of VEGF on the VEGFR-2 receptor. Inhibition of VEGFR-1 signaling is associated with preeclampsia, reduced fetal and placental weights and compromised arterial remodeling of the uterine circulation. The proposed studies seek to understand how gestation affects the signaling and functional downstream actions of VEGFR-1 activation by addressing four Specific Aims:
Aim 1 will define the effects of altered VEGFR-1 signaling on uterine blood flow and vascular remodeling.
Aim 2 will characterize the localization and molecular biology of this receptor in uterine arteries and veins as a function of gestation and vessel size, and determine how shear stress and estrogen affect its expression.
Aim 3 will elucidate the mechanisms by which VEGFR-1 activation produces arterial and venous vasodilation, with a focus on potassium channel involvement in membrane hyperpolarization, and on the molecular identity of the vasodilator molecules.
Aim 4 will determine the cellular pathway (para- vs. trans-cellular) and signaling mechanism by which VEGFR-1 activation amplifies uterine venous permeability. Four rat in vivo viral overexpression models (sVEGFR-1, sVEGFR-2, PlGF, VEGF) and a surgical uterine horn ligation model, in which implantation is restricted to one side of the uterus, will be used for these studies and combined with in vitro assessment of structural changes in arteries and veins, and of mechanisms underlying receptor regulation and signaling. The growth, vasodilation and increased permeability of uterine vessels all contribute to increasing uterine blood flow during gestation. This project will generate new insights into a physiological signaling pathway whose aberrance has been implicated in preeclampsia, insufficient uterine vascular remodeling, and an imbalance of vasoactive signals favoring excessive vasoconstriction.

Public Health Relevance

This project is an investigation of the biological actions of VEGFR-1, a receptor for the VEGF/PlGF growth factor family, in the uterine circulation during pregnancy. These studies are potentially important to women's health because dysregulation of VEGFR-1 has recently been associated with preeclampsia. Surprisingly little is known about its actions on the blood vessels of the uterus, and this project will determine the mechanisms by which it mediates uterine vascular changes during gestation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079253-04
Application #
8120685
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Mitchell, Megan S
Project Start
2008-09-01
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$379,117
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
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Mandala, Maurizio; Osol, George (2012) Physiological remodelling of the maternal uterine circulation during pregnancy. Basic Clin Pharmacol Toxicol 110:12-8
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Osol, George; Celia, Gerard; Gokina, Natalia et al. (2008) Placental growth factor is a potent vasodilator of rat and human resistance arteries. Am J Physiol Heart Circ Physiol 294:H1381-7