H2S and Uterine Vasodilation in Pregnancy and Preeclampsia

PROJECT SUMMARY
Once conceived, a woman’s cardiovascular system undergoes dramatic structural and functional changes to
accommodate the increasing demands of the fast growing fetus, resulting in profound uterine artery dilation
exemplified by dramatic rise in uterine blood flow (UBF). UBF is a rate-limiting factor for pregnancy health
because an insufficient rise in UBF during pregnancy is causative for intrauterine growth restriction and
preeclampsia (PE) characterized by systemic endothelial damage and vascular dysfunction. Since 1900’s,
numerous studies have concluded that local endothelial nitric oxide (NO)-mediated vasodilation is the major
mechanism controlling rise in UBF. However, blockade of local NO production only partially inhibits baseline
pregnancy-associated rise in UBF, suggesting that other mediator(s) are involved. Endogenous hydrogen
sulfide (H2S), mainly synthesized from L-cysteine by two key enzymes: cystathionine -synthase (CBS) and
cystathionine -lyase (CSE), is an extremely potent proangiogenic vasodilator. We initially posited that local
CBS/H2S production can fill the mechanism behind NO to mediate UA vasodilation during pregnancy. Indeed,
we reported that pregnancy dramatically augments UA H2S biosynthesis by selectively upregulating EC and
SM CBS but not CSE expression in animals (rats and ewes) and women in vivo and that H2S stimulates
pregnancy-dependent dilation of pressurized UA ex vivo. In animal models of PE and women with PE, we
found that pregnancy-augmented myometrial UA CBS/H2S is significantly downregulated. However, research
on H2S in uterine hemodynamics is still in its infancy; many important key questions need to be answered
before a physiological and a pathophysiological role of CBS/H2S signaling in normal pregnancy and PE can
be determined. In this new RO1 we propose to test a novel hypothesis that enhanced UA EC and SM
CBS/H2S production mediates pregnancy-associated UA dilation by interacting with vascular
endothelial growth factor and EC eNOS-NO and downregulated UA CBS/H2S signaling contributes to
the vascular dysfunction in PE. We will test this hypothesis by a multidisciplinary translational approach
with biochemical, cellular, molecular, physiological, and pharmacological methods coupled with rat models in
vivo, freshly isolated human and rat UA rings ex vivo, novel human UA EC (hUAEC) and smooth muscle cell
(hUASMC) models in vitro, and myometrial UAs from normotensive vs. PE pregnant women. We have an
outstanding team with a track record of long-term productive collaborative research in the field and unique
tools needed to complete this exciting and important project. We believe that the novel studies outlined in
this RO1 will provide new data to fill a knowledge gap on the physiological and pathophysiological role for
H2S in in uterine hemodynamic regulation and this knowledge will provide a compelling rationale for clinical
trials to explore the therapeutic potential of H2S in women in high risk of PE.

Grant Number: 5R01HD105699-05
NIH Institute/Center: NIH
Principal Investigator: DONGBAO CHEN