Vascular Mechanisms of Hypertension-in-Pregnancy

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Project Summary/Abstract Preeclampsia (PE) is a complication of pregnancy characterized by hypertension (HTN-Preg) and intrauterine growth restriction (IUGR), with unclear mechanism and limited remedies. We and others have shown that: reduction in uterine perfusion pressure (RUPP) and infusion of sFlt-1 or TNF in pregnant (Preg) rats reduce vascular relaxation and increase vasoconstriction (VC) and BP; however, the vascular and uterine targets are unclear. Normal pregnancy involves extensive uteroplacental and vascular remodeling, and matrix metalloproteinases (MMPs) and related A Disintegrin And Metalloprotease (ADAM) family maintain adequate tissue remodeling. We have found decreases in uteroplacental and vascular MMP-2 and -9, and increases in MMP-1 and -7 in RUPP, and sFlt-1 and TNF infused Preg rats. We have also discovered that MMPs not only degrade extracellular matrix (ECM) proteins, but also release peptide fragments, growth factors and ET-1 and in turn affect the Endothelium, Vascular smooth muscle (VSM) and ECM (EVE), such that MMP-2 and -9 are vasodilators (VD) while MMP-1 and -7 are vasoconstrictors (VC). Also, in search for the upstream mechanisms that trigger the changes in MMPs, our data suggest that ADAM-17, a sheddase and TNF converting enzyme, is increased in RUPP rats, and elevation of ADAM-17 causes MMP imbalance, and increases circulating TNF and sFlt-1, VC and BP in Preg rats. These new findings led us to the novel hypothesis that disruption of VD/VC MMP balance is a major mechanism of impaired EVE-dependent vascular pathways and HTN-Preg. Increased ADAM-17 activity triggers disruption of MMP balance. Consequently, correcting MMP imbalance by upregulating VD MMP-2 and -9 or downregulating VC MMP-1 and -7, or reducing the upstream ADAM-17 activity should improve EVE-dependent vascular pathways and HTN-Preg. Studies will be performed on Preg rats; RUPP, sFlt-1 and TNF-infused rat models of HTN-Preg; Preg rats treated with MMP-2 and -9 inhibitors, neutralizing antibody or siRNA or with ADAM-17, MMP-1 or -7; and MMP-2, -9 and -7 KO mice. Mechanistic studies at the whole animal, uteroplacental, microvascular and molecular levels will provide in-depth analysis of the mechanisms linking ADAM-17 and MMP imbalance to impaired EVE-dependent vascular pathways and HTN-Preg. The specific aims are to test the hypotheses that: 1) Disruption of VD/VC MMP balance during pregnancy is sufficient to impair EVE-dependent vascular pathways and cause HTN-Preg. 2) Increased ADAM-17 activity is an upstream mechanism that triggers disruption of VD/VC MMP balance, leading to impaired EVE-dependent vascular pathways and HTN-Preg. 3) Interventional correction of MMP imbalance and ADAM-17 activity is a central target to improve EVE-dependent vascular pathways and HTN-Preg. These studies should provide a better understanding of the role of MMP imbalance and ADAM-17 in HTN-Preg, and highlight potential usefulness of correcting MMP imbalance and ADAM-17 activity in the management of PE.