Mechanosensitive smooth muscle cell phenotypic plasticity emerging from a null state and the balance between Rac and Rho

Vascular smooth muscle cells (VSMCs) oscillate between a differentiated (contractile) and a de-differentiated (synthetic) phenotype.  In a healthy, mature vessel these VSMCs exist in a differentiated phenotype that comprises the portion of the vessel that contracts to help transport oxygenated blood; conversely, in response to injury, VSMCs can de-differentiate into a synthetic phenotype where they become proliferative and contribute to wound healing.  In a recent study by Talwar et al., the group discovered that VSMCs, under selective ECM conditions, can also exist in a null state and can be driven towards the conventional differentiated or de-differentiated phenotypes in response to Rac and Rho signaling.  The group used a combination of mathematical and computational modeling to identify a null VSMC phenotype.  They then utilized single cell experimental validation approaches that could capture both phenotypic and functional changes in response to ECM stiffness, which allowed them to identify VSMCs in soft ECM conditions that expressed low levels of smooth muscle actin (SMA), a marker of differentiation, while also being EdU negative (a proliferative, de-differentiated marker).  Rho and Rac constitutively active and inactive mutants were utilized to define their role in directing VSMC maturation from the null phenotype to the established differentiated and de-differentiated phenotypes.  The group also utilized acute stimulants like RhoA specific activator, CN03, to show that RhoA activation is sufficient to drive VSMCs from a null state to a differentiated, contractile state.  Interestingly, Rac can push null state VSMCs to either a differentiated or dedifferentiated state through its differential regulation of downstream YAP and TAZ transcription factors. Cytoskeleton’s G-switch RhoA activator (Cat. # CN03) was an essential tool to define RhoA’s role in VSMC phenotypic modulation.

Schematic of Rac and Rho’s influence on VSMC differentiation from a null state

Above:Schematic of Rac and Rho’s influence on VSMC differentiation from a null state