Vascular Mechanisms of Hypertension-in-Pregnancy

妊娠期高血压的血管机制

• 批准号: 10481866
• 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
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10481866
• 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; antagonist; blood pressure reduction; collagenase; cytokine; improved; inhibitor; neutralizing antibody; novel; novel strategies; pregnant; pressure; trophoblast; vasoconstriction

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.

项目摘要/摘要 抑制（PE）是以高血压（HTN-PREG）为特征的妊娠并发症，并且 插入生长限制（IUGR），具有不清楚的机制和有限的补救措施。我们和其他人有 表明：在怀孕（PREG）中，子宫灌注压力（RUPP）的降低和SFLT-1或TNF的输注 大鼠减少血管松弛并增加血管收缩（VC）和BP；但是，血管和子宫 目标尚不清楚。正常怀孕涉及广泛的子宫t和血管重塑，并且基质 金属蛋白酶（MMP）和相关的拆分蛋白和金属蛋白酶（ADAM）家族保持足够 组织重塑。我们发现子宫表和血管MMP -2和-9的下降，并增加 RUPP中的MMP-1和-7，SFLT-1和TNF注入Preg大鼠。我们还发现MMP不仅 降解细胞外基质（ECM）蛋白质，但也释放肽片段，生长因子和ET-1和 反过 血管扩张剂（VD）时MMP -1和-7是血管收缩器（VC）。另外，寻找上游机制 这触发了MMP的变化，我们的数据表明Adam-17，Shedase和Tnf转化酶， 在Rupp大鼠中增加，ADAM-17的升高会导致MMP失衡，并增加循环TNF Preg大鼠中的SFLT-1，VC和BP。这些新发现使我们提出了一个新的假设，即VD/VC的破坏 MMP平衡是EVE依赖性血管途径和HTN-PREG受损的主要机制。增加 Adam-17活性触发了MMP平衡的破坏。因此，通过 上调VD MMP-2和-9或下调VC MMP-1和-7，或减少上游ADAM-17 活性应改善依赖EVE的血管途径和HTN-PREG。研究将在PREG上进行 老鼠； HTN-PREG的Rupp，Sflt-1和tnf注入的大鼠模型；用MMP -2和-9抑制剂治疗的PEG大鼠， 中和抗体或siRNA或ADAM-17，MMP-1或-7；以及MMP -2，-9和-7 KO小鼠。机理 在整个动物，子宫遗传，微血管和分子水平的研究将提供深入分析 将ADAM-17和MMP失衡与依赖EVE依赖的血管途径和MMP失衡联系起来的机制 htn-preg。具体目的是测试以下假设：1）在 妊娠足以损害Eve依赖性血管途径并导致HTN-PREG。 2）增加 Adam-17活动是一种上游机制，可触发VD/VC MMP平衡的破坏，导致 依赖EVE的血管途径和HTN-PREG受损。 3）MMP不平衡的介入 ADAM-17活性是改善EVE依赖性血管途径和HTN-PREG的核心目标。这些 研究应更好地了解MMP失衡和ADAM-17在HTN-PREG中的作用，以及 强调纠正PE管理中MMP不平衡和ADAM-17活性的潜在有用性。