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Thrombospondin-1 Regulates Vascular Tone

Thrombospondin-1 调节血管张力

基本信息

批准号：
7911886
负责人：
Jeffrey S Isenberg
金额：
$ 21.49万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-17 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7911886
关键词：
Actins Acute Adhesions Angiogenesis Inhibitors Area Arteries Binding Blood Blood Platelets Blood Vessels Blood flow Brain Hypoxia-Ischemia CD36 gene CD47 gene Cell Surface Receptors Cell surface Cells Contractile Proteins Cyclic GMP Data Electron Spin Resonance Spectroscopy Endothelial Cells Extracellular Matrix Gases Growth Health In Vitro Ligation Malignant Neoplasms Measures Muscle relaxation phase Myosin Light Chains Necrosis Nitric Oxide Oxygen Perfusion Phosphorylation Play Regulation Relaxation Reporting Research Personnel Role Smooth Muscle Smooth Muscle Myocytes Soft Tissue Neoplasms Soluble Guanylate Cyclase Stress Structural Protein Therapeutic Agents Thrombospondin 1 Tissues Transgenic Mice Tumor Tissue Vascular blood supply Vasodilation base in vivo inhibitor/antagonist migration programs receptor response soft tissue

项目摘要

DESCRIPTION (provided by applicant): Blood vessels, as conduits for blood flow, control blood supply to a particular tissue area through alterations in their size. Such changes in vessel size are regulated by vascular smooth muscle cells (VSMC) which form a part of the wall of most blood vessels. Alterations in the contractility of VSMC directly change the size of blood vessels and can increase or decrease blood flow to tissues. Nitric oxide (NO) is a bioactive gas with wide ranging effects in the body. NO has been identified as a locally important regulator of VSMC contractility. These effects require stimulation of soluble guanylyl cyclase (sGC) by NO and result in rapid relaxation of VSMC. Thrombospondin-1 (TSP1) is a major regulator of vascular cell responses first identified as a secretory product from stimulated platelets. TSP1 is an important inhibitor of angiogenesis. We recently reported that TSP1 can block NO-driven effects in VSMC by blocking stimulation of sGC. Low levels of NO induce vascular cells to become hypersensitive to TSP1, with picomolar concentrations being sufficient to inhibit NO-stimulated VSMC cell responses. Based on our preliminary data we hypothesize that TSP1 regulates tissue blood flow and perfusion through control of NO-activated vascular smooth muscle cell contractility. In support of this hypothesis we propose three specific aims: 1) Demonstrate the effect TSP1 has upon contractile proteins in vascular smooth muscle cells. 2) Demonstrate the effects TSP1 has upon NO-driven vasorelaxation of VSMC. 3) Determine the effects of TSP1 on soft tissue perfusion and oxygen under ischemic stress. These studies should provide increased understanding of the role TSP1 plays in regulating vascular responses to nitric oxide and provide direction in developing therapeutic agents tailored to selectively regulate tissue perfusion.

描述（由申请人提供）：血管作为血流的导管，通过改变其大小来控制特定组织区域的血液供应。血管尺寸的这种变化由血管平滑肌细胞（VSMC）调节，血管平滑肌细胞形成大多数血管壁的一部分。VSMC收缩性的改变直接改变血管的大小，并可增加或减少流向组织的血流量。一氧化氮（NO）是一种生物活性气体，在体内具有广泛的作用。NO已被确定为VSMC收缩性的局部重要调节剂。这些作用需要通过NO刺激可溶性鸟苷酸环化酶（sGC）并导致VSMC快速松弛。血小板反应蛋白-1（TSP 1）是血管细胞反应的主要调节因子，最初被鉴定为刺激血小板的分泌产物。TSP 1是一种重要的血管生成抑制剂。我们最近报道TSP 1可以通过阻断sGC的刺激来阻断NO驱动的VSMC效应。低水平的NO诱导血管细胞变得对TSP 1过敏，皮摩尔浓度足以抑制NO刺激的VSMC细胞反应。基于我们的初步数据，我们假设，TSP 1通过控制NO激活的血管平滑肌细胞收缩性来调节组织血流和灌注。为了支持这一假设，我们提出了三个具体的目标：1）证明TSP 1对血管平滑肌细胞收缩蛋白的影响。2)证明TSP 1对NO驱动的VSMC血管舒张的影响。3)确定TSP 1对缺血应激下软组织灌注和氧的影响。这些研究应该提供更多的了解TSP 1在调节血管对一氧化氮的反应中所起的作用，并为开发选择性调节组织灌注的治疗药物提供方向。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Amyloid-β inhibits No-cGMP signaling in a CD36- and CD47-dependent manner.

DOI：
10.1371/journal.pone.0015686
发表时间：
2010-12-22
期刊：
PloS one
影响因子：
3.7
作者：
Miller TW;Isenberg JS;Shih HB;Wang Y;Roberts DD
通讯作者：
Roberts DD

Thrombospondin-1-CD47 blockade and exogenous nitrite enhance ischemic tissue survival, blood flow and angiogenesis via coupled NO-cGMP pathway activation.

DOI：
10.1016/j.niox.2009.05.005
发表时间：
2009-08
期刊：
Nitric oxide : biology and chemistry
影响因子：
0
作者：
Isenberg JS;Shiva S;Gladwin M
通讯作者：
Gladwin M

The matricellular protein thrombospondin-1 globally regulates cardiovascular function and responses to stress via CD47.

DOI：
10.1016/j.matbio.2012.01.005
发表时间：
2012-04
期刊：
MATRIX BIOLOGY
影响因子：
6.9
作者：
Roberts, David D.;Miller, Thomas W.;Rogers, Natasha M.;Yao, Mingyi;Isenberg, Jeffrey S.
通讯作者：
Isenberg, Jeffrey S.

Thrombospondin-1 inhibition of vascular smooth muscle cell responses occurs via modulation of both cAMP and cGMP.

血小板传播1对血管平滑肌细胞反应的抑制是通过调节CAMP和CGMP发生的。