title: Chronic cerebral hypoxia promotes arteriogenic remodeling events that can be identified by reduced endoglin (CD105) expression and a switch in β1 integrins.
abstract: 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 (α-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 β1 integrins (from α6 to α5), previously described for developmental angiogenesis. In vitro, transforming growth factor (TGF)-β1 also promoted this switch of BEC β1 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-β1 signaling, to promote a switch in β1 integrins and arteriogenic remodeling.
authors: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Amin
authors: A
authors: Boroujerdi
authors: Jennifer V
authors: JV
authors: Welser-Alves
authors: Ulrich
authors: U
authors: Tigges
authors: Richard
authors: R
authors: Milner
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000473:pathology*; D002908:Chronic Disease; D000071063:Endoglin; D042783:Endothelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D002534:Hypoxia, Brain / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D039081:Integrin alpha5beta1 / Q000378:metabolism; D039121:Integrin alpha6beta1 / Q000378:metabolism; D019012:Integrin beta1 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D000199:Actins; D000071063:Endoglin; C502004:Eng protein, mouse; D039081:Integrin alpha5beta1; D039121:Integrin alpha6beta1; D019012:Integrin beta1; D047908:Intracellular Signaling Peptides and Proteins; D053773:Transforming Growth Factor beta1