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.

项目概要/摘要 先兆子痫 (PE) 是一种妊娠并发症，其特征是高血压 (HTN-Preg) 和 宫内生长受限（IUGR），其机制尚不清楚且治疗方法有限。我们和其他人有 结果表明：孕妇 (Preg) 可以降低子宫灌注压 (RUPP) 并输注 sFlt-1 或 TNFα 大鼠减少血管舒张并增加血管收缩（VC）和血压；然而，血管和子宫 目标不明确。正常妊娠涉及广泛的子宫胎盘和血管重塑以及基质 金属蛋白酶 (MMP) 和相关的解整合素和金属蛋白酶 (ADAM) 家族保持足够的 组织重塑。我们发现子宫胎盘和血管 MMP-2 和 -9 减少，而 RUPP 中的 MMP-1 和 -7，以及 sFlt-1 和 TNFα 注入 Preg 大鼠中。我们还发现 MMP 不仅 降解细胞外基质 (ECM) 蛋白，同时释放肽片段、生长因子和 ET-1， 进而影响内皮细胞、血管平滑肌 (VSM) 和 ECM (EVE)，使得 MMP-2 和 -9 血管扩张剂 (VD)，而 MMP-1 和 -7 是血管收缩剂 (VC)。另外，寻找上游机制 触发 MMP 变化的因素，我们的数据表明 ADAM-17（一种脱落酶和 TNFα 转换酶） RUPP 大鼠中 ADAM-17 升高，ADAM-17 升高导致 MMP 失衡，并增加循环 TNFα Preg 大鼠中的 sFlt-1、VC 和 BP。这些新发现使我们提出了一个新假设：VD/VC 的破坏 MMP 平衡是 EVE 依赖性血管通路和 HTN-Preg 受损的主要机制。增加 ADAM-17 活动会触发 MMP 平衡的破坏。因此，通过以下方式纠正 MMP 失衡 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 EVE 依赖性血管通路和 HTN-Preg。研究将在 Preg 上进行 老鼠； HTN-Preg 的 RUPP、sFlt-1 和 TNFα 输注大鼠模型；用MMP-2和-9抑制剂治疗的Preg大鼠， 中和抗体或siRNA或与ADAM-17、MMP-1或-7；和MMP-2、-9和-7 KO小鼠。机械论 整个动物、子宫胎盘、微血管和分子水平的研究将提供深入的分析 ADAM-17 和 MMP 失衡与 EVE 依赖性血管通路受损之间的联系机制 HTN-预浸料。具体目的是检验以下假设： 1) VD/VC MMP 平衡在 妊娠足以损害 EVE 依赖性血管通路并导致 HTN-Preg。 2）增加 ADAM-17 活动是一种上游机制，会触发 VD/VC MMP 平衡的破坏，从而导致 EVE 依赖性血管通路和 HTN-Preg 受损。 3）MMP失衡的介入矫正 ADAM-17 活性是改善 EVE 依赖性血管通路和 HTN-Preg 的中心目标。这些 研究应能更好地理解 MMP 失衡和 ADAM-17 在 HTN-Preg 中的作用，以及 强调纠正 MMP 失衡和 ADAM-17 活性在 PE 管理中的潜在用途。