Endothelial Expression of β1 Integrin Is Required for Embryonic Vascular Patterning and Postnatal Vascular Remodeling

Abstract

The largest subgroup of integrins is that containing the ␤1 subunit. ␤1 integrins have been implicated in a wide array of biological processes ranging from adhesion to cell growth, organogenesis, and mechanotransduction. Global deletion of ␤1 integrin expression results in embryonic death at ca. embryonic day 5 (E5), a developmental time point too early to determine the effects of this integrin on vascular development. To elucidate the specific role of ␤1 integrin in the vasculature, we conditionally deleted the ␤1 gene in the endothelium. Homozygous deletion of ␤1 integrins in the endothelium resulted in failure of normal vascular patterning, severe fetal growth retardation, and embryonic death at E9.5 to 10, although there were no overt effects on vasculogenesis. Heterozygous endothelial ␤1 gene deletion did not diminish fetal or postnatal survival, but it reduced ␤1 subunit expression in endothelial cells from adult mice by approximately 40%. These mice demonstrated abnormal vascular remodeling in response to experimentally altered in vivo blood flow and diminished vascularization in healing wounds. These data demonstrate that endothelial expression of ␤1 integrin is required for developmental vascular patterning and that endothelial ␤1 gene dosing has significant functional effects on vascular remodeling in the adult. Understanding how ␤1 integrin expression is modulated may have significant clinical importance.The largest subgroup of integrins is that containing the ␤1 subunit (5, 6). ␤1 integrins have been implicated in a wide array of biological processes, including cell migration, adhesion, formation of basement membrane, and control of the cell cycle (5,6,11,13,20,25,31). They have also been purported to play an essential role in angiogenesis, although the data supporting this role have been obtained in an indirect manner using techniques such as blocking antibodies or RNA interference (15,22,30). The role of ␤1 integrin in angiogenesis has also been inferred by the finding that tumor formation by ␤1 null cells is defective, with absence of tumor vascularization (4). Further, ␤1 integrin expression is highly upregulated in the central nervous system vasculature during maturation, and it has thus been proposed that this integrin plays an important role in maintaining the integrity of the mature central nervous system vasculature (26). Interestingly, cerebral cavernous malformations (CCMs) have been linked to defects in the KRIT-1 gene, the protein product of which interacts with the integrin cytoplasmic domain-associated protein 1 alpha (ICAP-1␣) (24,(36)(37)(38). ICAP-1␣ directly binds the cytoplasmic tail of ␤1 integrin. Further, the ICAP-1␣ binding sites for both KRIT-1 and ␤1 integrin are similar, and both contain a crucial NPXY motif (36). It has thus been postulated that KRIT-1 and ␤1 integrin compete for binding to ICAP-1␣ and that this competition modulates ␤1 integrin signaling and function. Therefore, the vascular defects observed in patients with KRIT-1 gene mutations may involve abnormal ␤1 i...

Urocortin2 inhibits tumor growth via effects on vascularization and cell proliferation

“…Also of interest is that inhibition of ␣5␤1 integrin ligation increases PKA activation and may be an important mechanism whereby agents that alter intregrin function can inhibit angiogenesis (27). Recently we showed that endothelial cell-specific loss of the ␤1 integrin causes embryonic lethality and profound abnormalities in vascular development (28). It is interesting to consider that a PKA-mediated final common pathway may be involved in the vascular effects of Ucn2 and of altered integrin function.…”

Cell biology of embryonic migration

“…Illustrations were prepared by O. Karengina based on an image of a mouse embryo at E13.5. (Furuta, 1995;Ilic et al, 2003) Vinculin Focal adhesions Total Death by E10, with embryos displaying 30-40% reduction in size, lack of midline fusion of the rostral neural tube and developmental defects in heart, somites and limbs (Xu et al, 1998) Zyxin Focal adhesions Total Viable, fertile, no obvious abnormalities (Hoffman et al, 2003) α4 integrin Integrins Total Embryonic lethality, defects in placenta and vascular system, cardiac hemmorhages (Yang et al, 1995) αv integrin Integrins Total Partial embryonic lethality, intracerebral and intestinal hemorrhages and cleft palates (Bader et al, 1998) α5 integrin Integrins Total Embryonic lethal and E10-11 with migration-type defects in posterior trunk and yolk sac mesodermal structures (Yang et al, 1993) Lei et al, 2008;Tanjore, 2008) Total Death shortly after implantation (Fassler and Meyer, 1995) In vitro studies of cells from knockout mice…”

Small Rho GTPase-mediated actin dynamics at endothelial adherens junctions

“…45 This involves the polarity gene Par3 which is down regulated in b1-deficient endothelial cells and animals lacking endothelial b1 die at E9.5 and 10. 46 Recently, Barry and colleagues showed the importance of VE-cadherin and the small GTPase Cdc42 in opening the vascular lumen. 47 Hence, b1-integrins may be directly or indirecty linked to VEcadherin during vessel development.…”