Excess musularization of diseased vessels is a key component of diverse cardiovascular pathologies. Unfortunately, mechanisms underlying this vascular remodeling are not well delineated. Indeed, there has recently been extensive discussion and much controversy regarding the origins of cells in vascular lesions. We and others have demonstrated that SMCs in atherosclerotic plaques or hypoxia-induced hypermuscularized arterioles derive from clonal expansion of a SMC progenitor, and we recently identified a novel pool of SMC progenitors in arterioles of the mouse lung. These progenitors express SMC markers, such as smooth muscle myosin heavy chain (SMMHC), and the undifferentiated marker platelet-derived growth factor receptor (PDGFR)-?, and one to three of them are located at each muscular-unmuscular pulmonary arteriole border. Our preliminary studies suggest similar SMC marker+PDGFR-?+ cells are also present at the muscular transition zone in human and rat lung arterioles. We termed these cells as ?primed? (i.e., primed to muscularize); indeed, when a mouse is exposed to hypoxia, primed cells express the pluripotency factor Kruppel-like factor 4 (KLF4) and one of them migrates into the normally unmuscularized distal arteriole, downregulates SMMHC and clonally expands, giving rise to almost all the pathological distal SMCs. Elucidating the mechanisms underlying primed cell induction is a key step in our overall goal of improving the understanding of vascular disease pathogenesis and devising novel therapies. Hypoxia-induced transcription is largely regulated by the binding of hypoxia-inducible factors (HIFs) to hypoxia responsive regulatory elements, and SMC Hif1a deletion attenuates hypoxia-induced vascular remodeling. Our prior studies demonstrate that Klf4 knockout in SMCs prevents pulmonary arteriole remodeling. The 5' regulatory region of Klf4 contains a hypoxia responsive motif, and we suggest that HIF- induced upregulation of primed cell KLF4 is critical for distal muscularization. In addition, interaction of hypoxic ECs with primed cells undoubtedly is a critical component of the pathogenesis of hypoxia-induced remodeling. Thus, we hypothesize that primed cell progenitors are key players in pathological pulmonary vascular remodeling in diverse animals and that hypoxia-mediated primed cell induction is a result of both direct effects on primed cells and indirect effects via ECs. To test this hypothesis, we study isolated primed cells and ECs in co-culture, genetically engineered mice, rats as well as human lung tissue. These studies have three aims: i) elucidate direct effects of hypoxia on primed cells by analyzing the role of the HIF-KLF4 axis in primed cells on distal pulmonary arteriole muscularization; ii) determine indirect effects of hypoxia on primed cells by elucidating the mechanism of hypoxic EC-mediated effects on primed cells and distal pulmonary arteriole muscularization; and iii) identify primed cells in human and rat pulmonary arterioles and delineate their proliferation and gene expression during pulmonary vascular remodeling in the rat monocrotaline model.
Smooth muscle cells are an important component of normal blood vessels; however in diverse cardiovascular diseases, blood vessels remodel by accumulating excessive smooth muscle. The mechanisms underlying this pathological vascular remodeling are not well understood which limits therapeutic options. Herein, we investigate a newly identified smooth muscle cell progenitor pool that is critical for vascular remodeling, and hence, our studies promise to have profound implications on therapeutic strategies for diverse cardiovascular diseases.
