Focal adhesion signaling: vascular smooth muscle cell contractility beyond calcium mechanisms

Abstract

Smooth muscle cell (SMC) contractility is essential to vessel tone maintenance and blood pressure regulation. In response to vasoconstrictors, calcium-dependent mechanisms promote the activation of the regulatory myosin light chain, leading to increased cytoskeleton tension that favors cell shortening. In contrast, SMC maintain an intrinsic level of a contractile force independent of vasoconstrictor stimulation and sustained SMC contraction beyond the timescale of calcium-dependent mechanisms suggesting the involvement of additional players in the contractile response. Focal adhesions (FAs) are conceivable candidates that may influence SMC contraction. They are required for actin-based traction employed by cells to sense and respond to environmental cues in a process termed mechanotransduction. Depletion of FA proteins impairs SMC contractility, producing arteries that are prone to dissection because of a lack of mechanical stability. Here, we discuss the role of calcium-independent FA signaling mechanisms in SMC contractility. We speculate that FA signaling contributes to the genesis of a variety of SMC phenotypes and discuss the potential implications for mechanical homeostasis in normal and diseased states.

Role of Integrins in Modulating Smooth Muscle Cell Plasticity and Vascular Remodeling: From Expression to Therapeutic Implications

“…Integrin signaling plays an essential role in SMC biology by regulating adhesion, migration, proliferation, contraction, and differentiation [ 10 , 16 , 18 , 19 , 20 , 21 ]. Several proteins such as integrin-associated protein, integrin-linked kinase, focal adhesion kinase (FAK), tetraspanin CD9, and urokinase-type plasminogen activator receptor modulate integrin-mediated cell motility and adhesion in SMCs [ 10 , 22 , 23 , 24 , 25 ]. Integrin signaling in SMC also involves growth factor receptors that crosstalk between signaling pathways [ 17 , 26 ].…”

“…For instance, integrin–ligand adhesion triggers FAK auto-phosphorylation at tyrosine (Tyr) 397, which prompts FAK association with steroid receptor coactivator (Src). Src then phosphorylates other tyrosine residues that contribute to the full activation of FAK [ 25 ]. The activated FAK/Src complex facilitates various key signaling cascades, including the activation of serine-threonine protein kinase (AKT), extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein kinase (MAPK) pathway [ 30 , 31 ], all of which are known to regulate SMC proliferation and migration.…”

Mechanical programming of arterial smooth muscle cells in health and ageing

“…The ASMC contractile phenotype is found to be dependent on the expression of specific integrins (Zargham and Thibault 2006 ). In response to intraluminal pressure or cell adhesion–associated tension, focal adhesion kinase (FAK), a mechanosensitive component of FAs undergoes autophosphorylation (Lehoux et al 2005 ; Ribeiro-Silva et al 2021 ). Phosphorylated FAK activates Src and potentiates FA remodelling, via the phosphorylation of downstream signalling molecules paxillin (PXN) and CAS.…”

“…Phosphorylated FAK activates Src and potentiates FA remodelling, via the phosphorylation of downstream signalling molecules paxillin (PXN) and CAS. Once activated, pPXN and pCAS initiate actin polymerisation through a Rac/RhoA mediated pathway (Ribeiro-Silva et al 2021 ). FAs have been shown to be major regulators of ASMC contractility and tone.…”

“…As matrix rigidity increases during ageing, greater strain is placed onto FAs and vinculin is recruited to stabilise the FA-cytoskeleton linkage (Lacolley et al 2018 ). Further discussion on the role of FA complexes in regulating ASMC function, phenotype and ECM organisation can be found in recent reviews (Ohanian et al 2015 ; Lacolley et al 2018 ; Ribeiro-Silva et al 2021 ).…”