Integrin signaling in vascular function

TLDR: The role of integrins in angiogenesis has been demonstrated to include, in addition to cell adhesion and mechanotransduction, specific signaling functions, and endothelial permeability is directly regulated by this process.

Abstract: Integrins are crucial in vasculogenesis, angiogenesis, and vascular integrity as major mediators of vascular cell adhesion and migration through the extracellular matrix, as well as signaling co-receptors of the receptor tyrosine kinases, including VEGFR – the “master switch” of angiogenesis [1]. While studies determining unique versus redundant roles of a particular integrin pair are currently under way, utilization of tissue specific knockouts of integrin subunits has allowed an accurate assessment of integrin functions in endothelial and smooth muscle cells, as reviewed here. An important feature of integrins is the regulation of their affinity towards the extracellular matrix (ECM) ligands. In endothelial cells, integrin activation is induced by growth factors, including VEGF [1], and mechanical stress [2, 3]. Activation is achieved by binding two FERMT domain containing proteins, Talin and Kindlin, to NxxY motifs within the β integrin cytoplasmic domain. The role of Talin in integrin activation has been reported [4], however, the significance of Kindlin is demonstrated more recently [5–8] and will be further discussed in this review. Kindlin paralogs Kindlin-1, -2, and -3 have a high degree of sequence identity among them, yet exhibit different patterns of expression [9]. The presence of at least one Kindlin paralog is required to achieve integrin activation. Once integrins are engaged by ECM, they function as docking modules for a plethora of intracellular signaling proteins, altogether known as “adhesome” [10]. Integrin Linked Kinase (ILK) and Focal Adhesion Kinase (FAK) are required for the integrin link with the cytoskeleton and signal transduction. As global knockouts of ILK and FAK are lethal [11, 12], recently reported inducible and tissue specific knockouts of ILK and FAK have demonstrated the unique roles of these genes in smooth muscle and endothelial cells, respectively [13, 14].