Molecular Imaging of Vascular Remodeling

描述(申请人提供)：血管重塑，定义为血管大小和/或成分的持久变化，是许多血管疾病的共同特征，包括动脉粥样硬化、动脉瘤和移植物动脉硬化(GA)。血管平滑肌细胞(VSMC)的增殖和迁移以及基质支架的重组导致新生内膜增生和几何重构。炎症在发病机制中起着重要作用。在此，我们试图确定α-3整合素和基质金属蛋白酶(MMPs)激活与新生内膜增生和几何重构之间的功能意义。我们假设这种功能意义在不同形式的血管重塑中是有效的和相似的，即小鼠颈动脉丝损伤、GA和动脉瘤。我们的具体目的是：1)探讨α-3整合素和基质金属蛋白酶活化在VSMC和单核-巨噬细胞表型调控中的程度及其相互依赖关系；2)建立α-3和基质金属蛋白酶活化作为机械损伤诱导的血管重塑、GA和动脉瘤的共同介质的功能意义；3)评价α-3和基质金属蛋白酶显像在预测不同形式血管重塑重塑程度中的作用。A？3整合素和基质金属蛋白酶的活性将通过免疫染色和放射免疫分析法在分化和增殖的人VSMC以及静息单核细胞和1型和2型极化巨噬细胞中进行评估。A？3整合素和基质金属蛋白酶在VSMC和单核巨噬细胞中的相互激活和物理关联将被解决。免疫组织化学染色、Western blotting、酶谱和形态计量学方法将确定基质金属蛋白酶和α3的表达和激活及其与几何重塑和内膜增生的相关性。将确定激活的基质金属蛋白酶和α3的细胞来源，并使用特定的抑制剂证实它们的功能意义。NC100692，激活的α？3-和RP782，激活的基质金属蛋白酶靶向血管成像将被验证并作为实验工具用于研究血管重塑的分子机制。在纵向研究中，将通过双重示踪剂α3和基质金属蛋白酶靶向成像来评估α3和基质金属蛋白酶的活性。这将确立α3和基质金属蛋白酶激活作为血管重塑的共同介质的功能意义，并验证它们作为活体成像的靶点。最终，这可以通过早期监测和干预来改善对血管病人的护理。

DESCRIPTION (provided by applicant): Remodeling, defined as an enduring change in the size and/or composition of blood vessels, is a common feature of many vascular diseases, including atherosclerosis, aneurysm and graft arteriosclerosis (GA). Vascular smooth muscle cell (VSMC) proliferation and migration and matrix scaffold reorganization lead to neointimal hyperplasia and geometrical remodeling. Inflammation plays an important role in the pathogenesis. Here, we seek to establish the functional significance of a?¿3 integrin and materix metalloproteinase (MMP) activation in relation to neointimal hyperplasia and geometrical remodeling. We hypothesize this functional significance is valid and analogous in different forms of vascular remodeling, namely murine carotid wire injury, GA and aneurysm. Our specific aims are to: 1) investigate the extent of a?¿3 integrin and MMP activation and their interdependence in VSMC and monocyte-macrophage phenotypic modulation, 2) establish the functional significance of a?¿3 and MMP activation as common mediators of mechanical injury-induced vascular remodeling, GA and aneurysm, and 3) assess a?¿3 and MMP imaging for predicting the extent of remodeling in different forms of vascular remodeling. a?¿3 integrin and MMP activation will be assessed by immunostaining and radioimmunoassay in differentiated and proliferative human VSMC, as well as resting monocytes and types 1 and 2 polarized macrophages. Reciprocal activation and physical association of a?¿3 integrin and MMP in VSMC and monocytemacrophages will be addressed. MMP and a?¿3 expression and activation and their correlation with geometrical remodeling and intimal hyperplasia will be established by immunostaining, Western blotting, zymography, and morphometry. Cellular sources of activated MMP and a?¿3 will be identified, and their functional significance confirmed using specific inhibitors. NC100692, activated a?¿3 - and RP782, activated MMP-targeted vascular imaging will be validated and utilized as experimental tools to study the molecular mechanisms of vascular remodeling. a?¿3 and MMP activation will be assessed by dual tracer a?¿3 and MMP-targeted imaging in longitudinal studies. This will establish the functional significance of a?¿3 and MMP activation as common mediators of vascular remodeling, and validate them as targets for in vivo imaging. Ultimately, this can improve the care of vascular patients through early monitoring and intervention.