Unexpected Roles of Perivascular Cells in Angiogenesis and Cancer
Hess, Daniel, Biochemistry and Molecular Genetics - School of Medicine, University of Virginia
Owens, Gary, E0:MD-MPHY Mole Phys & Biophysics, University of Virginia
Annex, Brian, E1:UPG-MD-INMD CV Medicine, University of Virginia
Angiogenesis, or the growth of new blood vessels, is critical during homeostasis, adaptation to injury, and disease. Proper functioning of the vasculature, including angiogenesis, requires coordinated action of both endothelial cells (EC) and perivascular cells, including smooth muscle cells and pericytes (SMC-P). SMC-P display remarkable phenotypic plasticity, which allows them to contribute to angiogenesis, tissue repair and disease pathogenesis. However, mechanisms by which perivascular cells directly contribute to angiogenesis following tissue injury, and to diseases such as cancer, remain largely unexplored.
Herein, we investigate the role of perivascular cells in angiogenesis and cancer pathogenesis using several different mouse models. Through combined SMC-P lineage tracing and genetic knockout of single genes exclusively in SMC-P, we demonstrate that SMC-P knockout of the stem cell pluripotency gene Oct4 leads to significantly impaired angiogenesis following corneal burn or hindlimb ischemia. We also demonstrate that SMC-P knockout of the interleukin 1-receptor (IL-1R) has no significant effect on primary tumor growth or metastasis. However, knockout of IL-1R specifically in EC results in significantly impaired primary tumor growth.
My work demonstrates that loss of a single gene in SMC-P can have profound effects on angiogenesis, thus adding to a growing body of literature demonstrating the essential role of SMC-P to effective angiogenesis. Additionally, these studies demonstrate that a functional role for Oct4 in SMC-P is not limited to the setting of atherosclerosis but instead likely evolved because it conferred survival and reproductive success by enhancing angiogenesis. The finding that IL-1R in EC, but not SMC-P, promotes primary tumor growth builds on the idea that, while both EC and SMC-P play essential roles in angiogenesis, tissue repair and disease pathogenesis, they utilize unique, cell-specific mechanisms in the process. These studies add to the notion that future therapeutic approaches to modulate angiogenesis should target both EC and SMC-P function.
PHD (Doctor of Philosophy)
Perivascular cells, Angiogenesis, Cancer
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