Cell-autonomous requirement for β1 integrin in endothelial cell adhesion, migration and survival during angiogenesis in mice

Abstract

β1 integrin (encoded by Itgb1) is established as a regulator of angiogenesis based upon the phenotypes of complete knockouts of β1 heterodimer partners or ligands and upon antibody inhibition studies in mice. Its direct function in endothelial cells (ECs) in vivo has not been determined because Itgb1-/- embryos die before vascular development. Excision of Itgb1 from ECs and a subset of hematopoietic cells, using Tie2-Cre, resulted in abnormal vascular development by embryonic day(e) 8.5 and lethality by e10.5. Tie1-Cre mediated a more restricted excision of Itgb1 from ECs and hematopoietic cells and resulted in embryonic lethal vascular defects by e11.5. Capillaries of the yolk sacs were disorganized, and the endothelium of major blood vessels and of the heart was frequently discontinuous in mutant embryos. We also found similar vascular morphogenesis defects characterized by EC disorganization in embryonic explants and isolated ECs. Itgb1-null ECs were deficient in adhesion and migration in a ligand-specific fashion, with impaired responses to laminin and collagens, but not to fibronectin. Deletion of Itgb1 reduced EC survival, but did not affect proliferation. Our findings demonstrate thatβ1 integrin is essential for EC adhesion, migration and survival during angiogenesis, and further validate that therapies targeting β1 integrins may effectively impair neovascularization.

Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis

“…In line with these results, genetic evidence supports that b1-integrins are essential for in vivo angiogenesis [3,4,41,49,52]. Since silencing of Brag2 enhanced b1-integrin-dependent adhesion and a5b1-integrin surface expression, we investigated the underlying mechanisms affecting b1-integrin function in EC.…”

“…However, additional studies will be required to clarify the underlying molecular mechanisms in EC. Based on the fact that b1-integrins are essential for angiogenesis [4,49,52], we focused in the present study on the effects of Brag2 on b1-integrins in EC.…”

“…Beyond angiogenic growth factors, there is evidence that integrins are implicated in angiogenesis [23]. Specifically, endothelialrestricted deficiency of b1-integrins and of the a5-integrin subunit of the b1-integrins impairs in vivo angiogenesis [4,31,49,50,52]. However, the effects of increased integrindependent EC adhesion on angiogenesis are still elusive.…”

Integrin β1 controls VE-cadherin localization and blood vessel stability

“…The b1-subunit, which can partner with 12 different a-chains and plays a central role in cell-matrix adhesion, has been also investigated with EC-specific gene targeting approaches in mice. Constitutive targeting of Itgb1, the gene encoding integrin b1, in ECs was found to be incompatible with normal morphogenesis of the embryonic vasculature and survival beyond midgestation [12][13][14] . Although this work has established that endothelial Itgb1 gene function is required for angiogenic sprouting but not for the assembly of the first vessel primordia by vasculogenesis, insight into the precise function of integrin b1 in the regulation of angiogenesis was limited by early embryonic lethality.…”

VEGF-Directed Blood Vessel Patterning: From Cells to Organism

“…Genetic deletion of b1 integrin has been particularly informative, perhaps because several endothelial integrin heterodimers (i.e., a1, a2 a3, a4, a5, a6, av heterodimers with b1) are affected by loss of b1 integrin. Several studies showed that b1 loss in endothelial cells results in aberrant endothelial adhesion and migration, and consequent defects in angiogenesis and embryonic lethality (Tanjore et al 2007;Carlson et al 2008). Zovein et al (2010) specifically investigated effects of endothelial b1 loss on apical-basolateral polarity and reported that arteries are selectively affected.…”