An essential requirement for β1 integrin in the assembly of extracellular matrix proteins within the vascular wall

Abstract

β1 integrin has been shown to contribute to vascular smooth muscle cell differentiation, adhesion and mechanosensation in vitro. Here we showed that deletion of β1 integrin at the onset of smooth muscle differentiation resulted in interrupted aortic arch, aneurysms and failure to assemble extracellular matrix proteins. These defects result in lethality prior to birth. Our data indicates that β1 integrin is not required for the acquisition, but it is essential for the maintenance of the smooth muscle cell phenotype, as levels of critical smooth muscle proteins are gradually reduced in mutant mice. Furthermore, while deposition of extracellular matrix was not affected, its structure was disrupted. Interestingly, defects in extracellular matrix and vascular wall assembly, were restricted to the aortic arch and its branches, compromising the brachiocephalic and carotid arteries and to the exclusion of the descending aorta. Additional analysis of β1 integrin in the pharyngeal arch smooth muscle progenitors was performed using wnt1Cre. Neural crest cells deleted for β1 integrin were able to migrate to the pharyngeal arches and associate with endothelial lined arteries; but exhibited vascular remodeling defects and early lethality. This work demonstrates that β1 integrin is dispensable for migration and initiation of the smooth muscle differentiation program, however, it is essential for remodeling of the pharyngeal arch arteries and for the assembly of the vessel wall of their derivatives. It further establishes a critical role of β1 integrin in the protection against aneurysms that is particularly confined to the ascending aorta and its branches.

α5 and αv integrins cooperate to regulate vascular smooth muscle and neural crest functions in vivo

“…Itga5/av SM22-Cre embryos developed interrupted aortic arch type-B and a large aneurysm that encompassed the brachiocephalic artery and the proximal region of the right carotid artery. The same phenotype has been observed in mice that lack vSMC expression of all the β1 integrins (Turlo et al, 2012). This suggests that the phenotype of Itga5/ av SM22-Cre mice, and therefore the vSMC-specific Itgb1 mutant, is caused by the loss of α5β1 and specifically αvβ1, rather than any of the other αv (αvβ3, αvβ5, αvβ6 and αvβ8) or β1 (α1β1, α2β1, α3β1, α4β1, α6β1, α7β1, α9β1, α10β1, α11β1) integrin heterodimers.…”

“…This suggests that the phenotype of Itga5/ av SM22-Cre mice, and therefore the vSMC-specific Itgb1 mutant, is caused by the loss of α5β1 and specifically αvβ1, rather than any of the other αv (αvβ3, αvβ5, αvβ6 and αvβ8) or β1 (α1β1, α2β1, α3β1, α4β1, α6β1, α7β1, α9β1, α10β1, α11β1) integrin heterodimers. Like Turlo et al (2012), we also found that migration and initiation of vSMC fate were unaffected by loss of α5 and αv integrins. vSMCs in Itga5/av mutants expressed high levels of the vSMC markers αSMA, SM22α and Myh11, and migrated efficiently to the PAAs and blood vessels within the skin.…”

Neural crest cell-autonomous roles of fibronectin in cardiovascular development

“…Thus, the downregulation of integrins α5 and αv in Itga5/Itgav SM22-Cre double mutants has most likely occurred after the onset of VSMC differentiation in the NC, explaining the lack of VSMC differentiation defect in these mutants (Turner et al, 2015). Similarly, Turlo et al (2012) used the SM22α-Cre transgenic line to ablate integrin β1 and showed that the expression of β1-containing integrin heterodimers, which include α5β1, in smooth muscle cells was important for maintaining AAA VSMCs and AAA integrity. Taken together with the studies by Turlo et al (2012) and Turner et al (2015), our work demonstrates that signaling by Fn1 and integrin α5β1 is essential for both the morphogenesis and maintenance of the AAAs: our studies establish the requisite role of Fn1 and integrin α5β1 in the differentiation of NC cells into VSMCs, thereby regulating the remodeling of symmetrical PAAs into the AAAs.…”

“…Similarly, Turlo et al (2012) used the SM22α-Cre transgenic line to ablate integrin β1 and showed that the expression of β1-containing integrin heterodimers, which include α5β1, in smooth muscle cells was important for maintaining AAA VSMCs and AAA integrity. Taken together with the studies by Turlo et al (2012) and Turner et al (2015), our work demonstrates that signaling by Fn1 and integrin α5β1 is essential for both the morphogenesis and maintenance of the AAAs: our studies establish the requisite role of Fn1 and integrin α5β1 in the differentiation of NC cells into VSMCs, thereby regulating the remodeling of symmetrical PAAs into the AAAs. The work of Turlo et al (2012) and Turner et al (2015) demonstrated that following the differentiation of NC cells into VSMCs, signaling by α5-, αv-and β1-containing integrin heterodimers is essential for maintaining VSMCs and the architecture of the AAA vessel wall.…”

Epithelial cell integrin β1 is required for developmental angiogenesis in the pituitary gland

“…In postnatal retinal vasculature, integrin β1-mediated endothelial cell-ECM interactions were required for production and assembly of the ECM, as well as formation of stable, nonleaky blood vessels (11). Mural cells (pericytes and vascular smooth muscle cells) that encase blood vessels also must express integrin β1 for adhesion and spreading, as well as assembly of ECM proteins that stabilize blood vessel walls (12,13).…”