| Cardiovascular disease accounts for nearly 50% of deaths in the United States. Treatment options include angioplasty and stent or graft placement which frequently result in restenosis. Part of the restenotic response is the formation of a smooth muscle rich neointima. This thesis uses chimeric mouse models to examine the roles of platelet-derived growth factor receptor beta (PDGFRβ) and PDGF B-chain in formation of a neointima in injured vessels, granulation tissue formation, and angiogenesis.; PDGF is believed to play a role in the vascular response to injury, but it has proven difficult to distinguish whether it is stimulating cell migration or cell proliferation, and whether the action is direct or indirect. To determine this, chimeric mice, composed of both wild-type and marked PDGFRβ-deficient cells, were generated. The consequences of PDGFRβ expression for cell participation in injury induced neointima formation was determined. The proportion of PDGFRβ −/− SMCs increased in the media and decreased in the neointima, consistent with migration of WT SMCs out of the media and into the intima, leaving the PDGFRβ −/− cells behind. This demonstrates that the most significant direct role of PDGFRβ is to mediate responses that involve SMC migration and not proliferation.; Exogenous PDGF B-chain is able to augment wound repair and angiogenesis. To test the hypotheses that endogenous PDGF B-chain from platelets and macrophages (both rich in PDGF B-chain) promotes wound repair and neointima formation, chimeric mice, lacking PDGF B-chain in all cells of hematopoietic origin were created. Absence of hematopoietic PDGF B-chain did not decrease the extent of foreign body induced granulation tissue formation or vascular injury induced neointima formation. Lack of PDGF B-chain of hematopoietic origin paradoxically increased the vascularity of both granulation tissue and organized thrombi. This demonstrates that PDGF B-chain from cells of hematopoietic origin, including platelets and macrophages, is not important for granulation tissue or neointima formation. Lack of PDGF B-chain of hematopoietic origin reduces vascularization of granulation issue and organized thrombi, probably through disabling of the short-range chemotactic gradients of PDGF that are important for recruiting pericytes/SMCs to the endothelium of new vessels. |
