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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052309-05
Application #
6184261
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1996-05-10
Project End
2003-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
5
Fiscal Year
2000
Total Cost
$175,419
Indirect Cost
Name
University of Virginia
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Murfee, Walter L; Rehorn, Michael R; Peirce, Shayn M et al. (2006) Perivascular cells along venules upregulate NG2 expression during microvascular remodeling. Microcirculation 13:261-73
Skalak, Thomas C (2005) Angiogenesis and microvascular remodeling: a brief history and future roadmap. Microcirculation 12:47-58
Murfee, Walter L; Hammett, Laura A; Evans, Caroline et al. (2005) High-frequency, low-magnitude vibrations suppress the number of blood vessels per muscle fiber in mouse soleus muscle. J Appl Physiol 98:2376-80
Murfee, Walter L; Skalak, Thomas C; Peirce, Shayn M (2005) Differential arterial/venous expression of NG2 proteoglycan in perivascular cells along microvessels: identifying a venule-specific phenotype. Microcirculation 12:151-60
Peirce, Shayn M; Price, Richard J; Skalak, Thomas C (2004) Spatial and temporal control of angiogenesis and arterialization using focal applications of VEGF164 and Ang-1. Am J Physiol Heart Circ Physiol 286:H918-25
Murfee, Walter L; Van Gieson, Eric J; Price, Richard J et al. (2004) Cell proliferation in mesenteric microvascular network remodeling in response to elevated hemodynamic stress. Ann Biomed Eng 32:1662-6
Longo, Diane; Peirce, Shayn M; Skalak, Thomas C et al. (2004) Multicellular computer simulation of morphogenesis: blastocoel roof thinning and matrix assembly in Xenopus laevis. Dev Biol 271:210-22
Van Gieson, Eric J; Murfee, Walter L; Skalak, Thomas C et al. (2003) Enhanced smooth muscle cell coverage of microvessels exposed to increased hemodynamic stresses in vivo. Circ Res 92:929-36
Peirce, Shayn M; Skalak, Thomas C (2003) Microvascular remodeling: a complex continuum spanning angiogenesis to arteriogenesis. Microcirculation 10:99-111
Van Gieson, E J; Skalak, T C (2001) Chronic vasodilation induces matrix metalloproteinase 9 (MMP-9) expression during microvascular remodeling in rat skeletal muscle. Microcirculation 8:25-31

Showing the most recent 10 out of 22 publications