Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 32, Issue 9, Pages 1820-1830Publisher
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2012.94
Keywords
angiogenesis; arteriogenesis; cell adhesion; endothelium; receptor; vascular biology
Categories
Funding
- National Multiple Sclerosis Society [JF 2125A1/1]
- NIH [NS060770]
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Chronic cerebral hypoxia leads to a strong vascular remodeling response, though little is known about which part of the vascular tree is modified, or whether this response includes formation of new arterial vessels. In this study, we examined this process in detail, analyzing how hypoxia (8% O-2 for 14 days) alters the size distribution of vessels, number of arteries/arterioles, and expression pattern of endoglin (CD105), a marker of angiogenic endothelial cells in tumors. We found that cerebral hypoxia promoted the biggest increase in the number of medium to large size vessels, and this correlated with increased numbers of alpha smooth muscle actin (alpha-SMA)-positive arterial vessels. Surprisingly, hypoxia induced a marked reduction in CD105 expression on brain endothelial cells (BECs) within remodeling arterial vessels, and these BECs also displayed an angiogenic switch in beta 1 integrins (from alpha 6 to alpha 5), previously described for developmental angiogenesis. In vitro, transforming growth factor (TGF)-beta 1 also promoted this switch of BEC beta 1 integrins. Together, these results show that cerebral hypoxia promotes arteriogenesis, and identify reduced CD105 expression as a novel marker of arteriogenesis. Furthermore, our data suggest a mechanistic model whereby BECs in remodeling arterial vessels downregulate CD105 expression, which alters TGF-beta 1 signaling, to promote a switch in beta 1 integrins and arteriogenic remodeling. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 1820-1830; doi:10.1038/jcbfm.2012.94; published online 27 June 2012
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