Vascular Precursors and Cell-Cell Signaling in Heart Vasculogenesis

描述(由申请人提供)：越来越多的证据表明，心脏病发作后功能的恢复明显受到梗死区血管重建的影响，这会影响损伤的程度、梗死区内的纤维化程度、损伤后的重塑和心律失常的发生率。尽管血管重建很重要，但血管生成和/或血管生成的过程仍然知之甚少，包括前体细胞参与新血管形成的程度，这些假定的前体细胞(如骨髓或常驻外膜细胞)的来源，以及控制归巢、命运和内皮细胞(EC)有丝分裂等过程的信号。这项建议考察了体内脑梗塞后血管重建的基本方面，利用了对血管前体的理解和遗传规范方面的最新进展。我们的中心假设是，梗塞触发内源性血管前体的扩张和分化，而内源性血管前体是通过血管周围生态位内关键的异型细胞-细胞相互作用而诱导的。这些实验将确定这些前体驱动血管重建的程度，确定它们的发育来源，并确定c-Kit、SCF、SCA1和SDF-1α/CXCR4信号的表达在这一过程中的作用。确定的前体群体和终末分化的血管细胞(内皮和平滑肌)将被基因标记，并检查梗死后新生血管细胞的谱系，以确定血管生成和血管生成的作用。C-kit及其配体干细胞因子(SCF)以及其他受体酪氨酸激酶的作用将在条件缺失(SCF)小鼠中进行检测。在基因敲除或有条件灭活的小鼠中，心肌和骨髓CXCR4信号的重要性将在基因敲除或条件灭活小鼠中确定。这些实验将为理解心脏缺血再血管化建立一个概念框架，这是制定旨在加强血管修复的治疗策略的关键一步。

DESCRIPTION (provided by applicant): There is increasing evidence that recovery of function following a heart attack is markedly influenced by revascularization of the infarcted region, which influences the extent of injury, the degree of fibrosis within the infarct, post injury remodeling, and the incidence of arrhythmia. Despite the importance of revascularization, the processes underlying angiogenesis and/or vasculogenesis remain poorly understood, including the degree to which precursor cells are involved in new vessel formation, the origin of these putative precursors (e.g. bone marrow or resident adventitial cells), and the signals that govern processes such as homing, fate, and endothelial cell (EC) mitosis. This proposal examines fundamental aspects of post-infarction revascularization in vivo, exploiting recent advances in the understanding and genetic specification of vascular precursors. Our central hypothesis is that infarction triggers the expansion and differentiation of endogenous vascular precursors that are induced through key heterotypic cell-cell interactions within the perivascular niche. The proposed experiments will identify the degree to which these precursors drive revascularization, determine their developmental origin, and establish the role of the expression of c-kit, SCF, Sca1, and SDF-1α/CXCR4 signaling in this process. Defined precursor populations and terminally differentiated vascular cells (endothelial and smooth muscle) will be genetically tagged and the lineage of post-infarct nascent vascular cells examined to determine the role of angiogenesis and vasculogenesis. The role of c-kit and its ligand stem cell factor (SCF), as well as other receptor tyrosine kinases, will be examined in conditionally deleted (SCF) mice. Heterotypic signaling functions of Sca1 cells that home to infarcts and are used for cell therapy, and the importance of cardiac and marrow CXCR4 signaling will be determined in knockout or conditionally inactivated mice. These experiments will establish a conceptual framework for the understanding of ischemic revascularization of the heart, a critical step in the development of therapeutic strategies directed toward enhancing vascular repair.