Vascular Precursors and Cell-Cell Signaling in Heart Vasculogenesis
Principal Investigator: Michael Kotlikoff
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-1aCXCR4 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.