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Vascular Mechanisms of Hypertension-in-Pregnancy

妊娠期高血压的血管机制

基本信息

批准号：
9974001
负责人：
Raouf A Khalil
金额：
$ 72.27万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9974001
关键词：
Affect Angiogenic Factor Animals Blood Vessels Collagen Cyclic AMP Cyclic GMP Data Deposition Disintegrins Down-Regulation Endothelin-1 Endothelium Endothelium-Dependent Relaxing Factors Enzymes Epoprostenol Equilibrium Etanercept Extracellular Matrix Extracellular Matrix Proteins Failure Family Fetal Growth Retardation Gelatinase A Gelatinases Growth Factor Hypertension Impairment Inflammatory Infusion procedures Integrins Interstitial Collagenase Intervention Knockout Mice Link Matrilysin Matrix Metalloproteinases Metalloproteases Modeling Molecular Mus Muscle Contraction PGF gene Pathway interactions Peptide Fragments Perfusion Pre-Eclampsia Pregnancy Pregnancy Complications Protein Kinase C Rattus Recombinants Relaxation Rho-associated kinase Role Signal Transduction Small Interfering RNA Spiral Artery of the Endometrium TNF gene TNF-alpha converting enzyme Testing Tissues Up-Regulation Uterus Vascular Diseases Vascular Smooth Muscle Vascular remodeling Vasoconstrictor Agents Vasodilation Vasodilator Agents blood pressure reduction collagenase cytokine improved inhibitor/antagonist neutralizing antibody novel novel strategies pregnant pressure trophoblast vasoconstriction

项目摘要

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.

项目总结/文摘