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  • br Acknowledgment br Introduction Vascular smooth muscle

    2024-07-10


    Acknowledgment
    Introduction Vascular smooth muscle cells (VSMC) exhibit the capacity to switch between a differentiated (contractile) and a dedifferentiated (synthetic) phenotype [1]. Synthetic VSMC express a lower amount of contractile proteins such as Smooth muscle 22α (sm22α) and α-Smooth muscle estrogen receptor antagonist (αSMA), but migrate and proliferate faster than their contractile counterpart. Although phenotypic switching of VSMC into their synthetic form might be useful for physiological processes such as vascular repair after injury, uncontrolled proliferation and migration of VSMC are responses contributing to the development of cardiovascular diseases, including atherosclerosis and vascular restenosis following angioplasty. In order to improve current therapeutics and clinical outcomes, it is important to better elucidate the mechanism that controls VSMC phenotypic modulation. A plethora of extracellular stimuli such as growth factors can modulate properties of VSMC [2,3]. Platelet-Derived Growth Factor (PDGF) stimulation promotes the synthetic phenotype [2] while the Insulin-like Growth Factor (IGF) promotes the contractile phenotype [3]. In addition, adhesion to the matrix plays an important part in phenotypical regulation. For instance, cells cultured on laminin and type IV collagen were shown to have increased expression of contractile proteins, while fibronectin, collagen type I and collagen type III had opposite effects [4,5]. Transmission of mechanical stress applied to VSMC, which is dependent upon focal adhesions that link integrins to the actin cytoskeleton, also controls their phenotype [6]. Notably, mechanical stretch through an application of intraluminal pressure was required to maintain contractile protein expression in aortic organ cultures [7]. While filamentous actin (F-actin) can mechanically transfer stress along the smooth muscle, its unpolymerized globular form (G-actin) can however act as a signaling intermediate. Indeed, the RPEL domain can bind to actin monomers, enabling the proteins possessing this domain to be reactive to G-actin levels [8]. Particularly, the serum response factor (SRF) co-activator Mkl1 (also known as Myocardin-related transcription factor A or MRTF-A) is negatively regulated by G-actin, where high globular actin levels in the cell will promote the sequestration of this co-activator away from the nucleus and into the cytoplasm [9,10]. In the nucleus, Mkl1 binds to the SRF transcription factor and induces transcription of contractile target genes [11]. High amounts of monomeric actin therefore lead to reduced transcription of contractile markers. Consequently, when not in complex with Mkl1, SRF will be directed to other target genes [12]. For instance, SRF promotes cell growth when in complex with the MAP kinase stimulated co-activator Elk-1, which further contributes to the synthetic phenotype. These evidences highlight the important role actin dynamic plays in the regulation of VSMC phenotype. ADP-ribosylation factors (ARF) are small GTPases of the Ras superfamily, known as molecular switches that can control phospholipid generation, vesicular trafficking and receptor signaling. Most importantly, these small G proteins have been shown multiple times to regulate actin cytoskeleton reorganization [[13], [14], [15], [16], [17]]. Six ARF isoforms were identified and ARF1 together with ARF6 remains the most studied [18]. Our previous work has shown that ARF6 controls both the migration [19] and proliferation [20] of VSMC, making this protein a candidate target for the treatment of vascular disorders. Like all GTPases, ARF cycles between an inactive (GDP-bound) and an active (GTP-bound) state. Loading of GTP is dependent upon ARF guanine nucleotide exchange factors (GEF) such as the cytohesin family of proteins. Both ARF1 and ARF6 activation can be blocked by the small molecule SecinH3, a potent inhibitor of the cytohesins [21]. This specific compound was reported to be effective in inhibiting growth of human lung cancer cells in vitro, but to also show anti-proliferative effects in vivo [22]. Whether ARF inhibition would be effective in preventing the dedifferentiation of VSMC during the pathological process remains to be determined.