Focal Adhesions

Abstract

Abstract-The vascular wall contains intimal endothelium and medial smooth muscle that act as contiguous tissues withtight spatial and functional coordination in response to tonic and episodic input from the bloodstream and the surrounding parenchyma. Focal adhesions are molecular bridges between the intracellular and extracellular spaces that integrate a variety of environmental stimuli and mediate 2-way crosstalk between the extracellular matrix and the cytoskeleton. Focal adhesion components are targets for biochemical and mechanical stimuli that evoke crucial developmental and injury response mechanisms including cell growth, movement, and differentiation, and tailoring of the extracellular microenvironment. Focal adhesions provide the vascular wall constituents with flexible and specific tools for exchanging cues in a complex system. The molecular mechanisms that underlie these vital communications are detailed in this review with the goal of defining future targets for vascular tissue engineering and for the therapeutic modulation of disordered vascular growth, inflammation, thrombosis, and angiogenesis. Four major factors influence the assembly rate, size, specific constituency, signaling repertoire, and functional impact of FAs. These are (1) the biophysical and biochemical properties of the ECM, (2) integrin activation and avidity, (3) the contraction state of the cytoskeleton, and (4) the specific cellular and tissue milieu in which these events occur.

Signal Transduction in Cerebral Arteries after Subarachnoid Hemorrhage—A Phosphoproteomic Approach

“…These complexes integrate biochemical and mechanical stimuli, including shear force, cyclic stretch, and contractile state of the vascular wall, into intracellular signals and changes in actin cytoskeleton dynamics, with FAK as a key activator of downstream signals. 29 We demonstrate for the first time regulation of FAK in cerebral arteries after SAH both at the autophosphorylation site Tyr397, indicating kinase activation, and at the regulatory phosphosite Ser910, the latter mediated by ERK1/2 in accordance with earlier studies. 30,31 Other examples of identified SAH-regulated focal adhesion proteins are Tensin-1 and PDZ and LIM domain protein 1, both linkers between signaling pathways and the cytoskeleton.…”

“…35 FAK is known to be regulated by a variety of mechanical and biochemical stimuli. 29 We speculate that the dramatic changes in hemodynamic forces acting on the vascular wall during acute SAH may induce FAK activation. Interestingly, a recent study from our laboratory demonstrated that the lack of vascular wall tension during organ culture of cerebral arteries induces smooth muscle FAK activation and downstream ERK1/2 activation, which again induces upregulation of contractile ET B receptors.…”

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

“…In this capacity, focal adhesion signaling has been implicated in the regulation of cellular processes such as cell migration, proliferation, differentiation, survival and gene expression, [24,44,46].…”

“…This aggregation of integrins in turn, recruits and activates signaling molecules FAK, Src and components of the Ras/MAPK pathway, as well as scaffolding proteins such as paxillin, vinculin and talin, resulting in the formation of focal adhesion complexes [40,46]. However, integrins are lacking in both catalytic activity and the ability to bind the actin cytoskeleton directly [24,46].…”

“…However, integrins are lacking in both catalytic activity and the ability to bind the actin cytoskeleton directly [24,46]. Therefore, the focal adhesion complex provides an interface through which extracellular signals can be amplified, and the cytoskeleton reorganized [24,46].…”