In vascular smooth muscle cells (VSMCs), actomyosin- and microtubule (MT)-derived forces balance each other. During aortic ageing, stiffening of the extracellular matrix (ECM) increases actomyosin-driven traction forces in VSMCs, opening stretch-activated ion channels such as PIEZO1. These channels tightly control Ca2+ influx to drive contraction under healthy conditions, but this process is dysregulated by stiffening of the ECM, leading to cell hypertrophy and reduced aortic compliance. How MTs contribute to these pathological changes is unclear. In this study (Johnson, Wostear, Solanki et al., 2024), Derek Warren and colleagues test the responses of MTs in VSMCs cultured on pliable or rigid substrates. They show that angiotensin II stimulation preferentially destabilises MTs in VSMCs on rigid substrates, but knockdown of PIEZO1 or depletion of extracellular Ca2+ under these conditions restores MT stability. Furthermore, modulating MT stability affects VSMC volume differently in cells on rigid versus pliable substrates: MT-stabilising drugs decrease VSMC volume and suppress Ca2+ flux only on rigid substrates, whereas MT-destabilising drugs increase VSMC volume and prolong Ca2+ flux only on pliable substrates. These results support a ‘tensegrity’ equilibrium model in which actomyosin contractile forces are balanced by compression-bearing MTs in VSMCs. Therefore, disequilibrium resulting from altered MT dynamics in response to the mechanochemical cues associated with aortic stiffening could potentially drive pathologic VSMC hypertrophy.
