Absence of the αvβ3 Integrin Dictates the Time-Course of Angiogenesis in the Hypoxic Central Nervous System: Accelerated Endothelial Proliferation Correlates with Compensatory Increases in α5β1 Integrin Expression

Abstract

Cerebral angiogenesis is an important adaptive response to hypoxia. As the alpha v beta 3 integrin is induced on angiogenic vessels in the ischemic central nervous system (CNS), and the suggested angiogenic role for this integrin in other systems, it is important to determine whether the alpha v beta 3 integrin is an important mediator of cerebral angiogenesis. alpha v beta 3 integrin expression was examined in a model of cerebral hypoxia, in which mice were subject to hypoxia (8% O(2)) for 0, 4, 7, or 14 days. Immunofluorescence and western blot analysis revealed that in the hypoxic CNS, alpha v beta 3 integrin was strongly induced on angiogenic brain endothelial cells (BEC), along with its ligand vitronectin. In the hypoxia model, beta 3 integrin-null mice showed no obvious defect in cerebral angiogenesis. However, early in the angiogenic process, BEC in these mice showed an increased mitotic index that correlated closely with increased alpha 5 integrin expression. In vitro experiments confirmed alpha 5 integrin upregulation on beta 3 integrin-null BEC, which also correlated with increased BEC proliferation on fibronectin. These studies confirm hypoxic induction of alpha v beta 3 integrin on angiogenic vessels, but suggest distinct roles for the BEC integrins alpha v beta 3 and alpha 5 beta 1 in cerebral angiogenesis, with alpha v beta 3 having a nonessential role, and alpha 5 beta 1 promoting BEC proliferation.

Slit2/Robo4 Signaling Modulates HIV-1 gp120-Induced Lymphatic Hyperpermeability

“…α 5 β 1 and α v β 3 are two major integrins expressed on the surface of endothelial cells [45]. We and others have shown that integrin α 5 β 1 , but not α v β 3 , clustered in focal contacts of endothelial cells during stressful cellular conditions (Figure 4B) or incubation with fibronectin [58]–[60]. In this study, we found that Robo4 formed a complex with fibronectin and integrin α 5 β 1 at low, basal levels in uninfected lymphatic endothelial cells (Figures 2B, 5A and 5B).…”

Extensive vascular remodeling in the spinal cord of pre-symptomatic experimental autoimmune encephalomyelitis mice; increased vessel expression of fibronectin and the α5β1 integrin

“…In previous studies, we showed that angiogenic vessels in the hypoxic and ischemic CNS strongly upregulate expression of fibronectin and its receptor α5β1 integrin (Li et al 2010b; Milner et al 2008a). Now, we addressed whether this holds true for remodeling vessels in the spinal cord of EAE mice.…”

Upregulation of fibronectin and the α5β1 and αvβ3 integrins on blood vessels within the cerebral ischemic penumbra

“…We have shown that angiogenic vessels in the hypoxic CNS strongly upregulate expression of fibronectin and its receptors, α5β1 and αvβ3 (Li et al 2010; Milner et al 2008a). Now, we addressed whether a similar induction also occurs on angiogenic vessels in the ischemic CNS.…”

“…To determine whether this developmental program is recapitulated during angiogenesis in the adult CNS, we recently examined this process in a mouse model of cerebral hypoxia, in which a strong physiological angiogenic response occurs. This revealed strong induction of fibronectin and the two fibronectin receptors, α5β1 and αvβ3 integrins on angiogenic vessels (Li et al 2010; Milner et al 2008a). More recently, we have demonstrated the functional significance of these interactions, by showing that mice deficient in endothelial cell expression of the α5 integrin, show an attenuated angiogenic response to chronic cerebral hypoxia (Li et al, manuscript in preparation).…”