Microvascular remodeling plays a central role in vascular biology because it is an essential mechanism enabling normal vascular adaptation in exercise and wound healing, as well as compensation for myocardial infarction, stroke, and trauma. Despite intensive effort that has been focused on capillary growth and collateral formation in pathological states, the origin of new arterioles that are formed in mature tissues was only recently identified. This study is designed to test the central hypothesis that extravascular fibroblasts are recruited to microvessels and undergo spatially-regulated differentiation under the control of stress-mediated cytokines during in vivo arteriolar pattern formation. The long-term objective is to advance understanding of the molecular mechanisms mediating remodeling of complete arteriolar networks in response to hemodynamic stresses in vivo.
The specific aims of the research are to determine the sites and time sequence of extravascular fibroblast recruitment and differentiation to a vascular smooth muscle phenotype during the development of new arterioles in vivo, to establish the role of intravascular stresses in fibroblast recruitment and differentiation in remodeling of the microvascular network in vivo, to determine whether fibroblast recruitment or differentiation is mediated by cytokine expression at arterialization sites in the microvascular network during chronic elevation of wall stress, by using blocking antibodies to PDGF and TGF-beta in a novel pre-labeled mesenteric window assay, and to use a mathematical computer network simulation of the microvascular networks produced in the experimental studies to test the hypothesis that circumferential wall stress is an important determinant of arteriolar pattern formation in vivo. The proposed experiments use an innovative and unique in vivo technique for assessing vascular contractile cell lineage during arteriolar network adaptation to controlled hemodynamic stress stimuli in the adult animal. Not only has this method provided the first demonstration of recruitment of native mesenchymal cells to newly-formed arterioles in vivo, but the technique represents a new experimental platform that opens the way for in vivo study of molecular regulation of arteriolar formation and collateralization, a subject of vast therapeutic importance.
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