Mechanosensitive cGMP signaling in vascular smooth muscle cells

Hypertension is an important risk factor for the development of vascular diseases. NO/NO-sensitive guanylyl cyclase (NO-GC)/cGMP signaling, a major mechanism of vasodilatation, affects blood pressure by regulating the relaxation of vascular smooth muscle cells (VSMCs). Under (patho-)physiological conditions, VSMCs are exposed to mechanical forces such as shear stress and stretch. Based on our recent discovery of mechanosensitive NO/cGMP signaling in platelets, we hypothesized that mechanical forces may also affect the NO/cGMP axis in VSMCs and aid in maintaining appropriate cGMP levels, thereby contributing to vascular homeostasis. To investigate the mechano-modulation of cGMP in real time, we used cells and tissues isolated from transgenic mice that express a FRET-based cGMP sensor. Recording of NO-dependent cGMP signals in primary aortic VSMCs under flow and static conditions demonstrated a potentiation of cGMP signals by fluid shear stress in many but not all VSMCs. Similarly, pressure puffs, another type of mechanical force, increased NO-induced cGMP signals depending on the magnitude of the applied pressure. Moreover, an exvivo model of mounted carotid arteries showed concentration-dependent cGMP responses to NO under flow, which were further enhanced by increasing the intravascular pressure. Thus, different types of mechanical stress increase NO-induced cGMP concentrations in VSMCs in culture and intact vessels. Additional studies are needed to dissect the molecular make-up and mode of action of mechano-sensitive cGMP signalosomes in VSMCs. Together, our data demonstrate the presence of a mechano-sensitive NO/NO‑GC/cGMP axis in VSMCs, which might be a target for the treatment of vascular diseases.