Thrombospondin-1 Regulates Vascular Tone

描述(申请人提供)：血管，作为血液流动的管道，通过改变其大小来控制对特定组织区域的血液供应。血管大小的这种变化是由血管平滑肌细胞(VSMC)调节的，VSMC是大多数血管壁的一部分。VSMC收缩能力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已被认为是局部重要的VSMC收缩调节因子。这些作用需要NO刺激可溶性鸟苷酸环化酶(SGC)，从而导致VSMC的快速松弛。血栓反应蛋白-1(TSP1)是血管细胞反应的主要调节因子，最初被认为是刺激的血小板分泌的产物。TSP1是一种重要的血管生成抑制因子。我们最近报道，TSP1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诱导血管细胞对TSP1高度敏感，皮摩尔浓度足以抑制NO刺激的VSMC细胞的反应。根据我们的初步数据，我们假设TSP1通过控制NO激活的血管平滑肌细胞的收缩来调节组织的血流和灌流。为了支持这一假设，我们提出了三个具体的目标：1)证明TSP1对血管平滑肌细胞收缩蛋白的影响。2)证实TSP1对NO诱导的VSMC血管松弛的影响。3)测定TSP1对缺血应激下软组织血流和氧含量的影响。这些研究应该能加深对TSP1在调节血管对一氧化氮反应中的作用的理解，并为开发选择性调节组织血流的治疗剂提供方向。

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.