Mechanosensitive cGMP signaling in vascular smooth muscle cells

• Applicants: Professor Dr. Robert Feil; Professorin Dr. Bettina Weigelin
• Subject Area: Pharmacology ; Anatomy and Physiology ; Biochemistry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563176411

A balanced activity of NO-cGMP signaling is critical for cardiovascular homeostasis in humans. Activation of this pathway in vascular smooth muscle cells (VSMCs) results in vasodilation and modulates VSMC growth and phenotype in the context of vascular diseases. Using technology to “watch” cGMP signals in real time in living cells, we have recently discovered that NO-induced cGMP production in platelets is strongly potentiated by shear stress and acts as a shear-dependent brake of thrombosis. Thus, we propose a new concept of mechanosensitive cGMP signaling, “mechano-cGMP”. Our preliminary live-cell imaging data in VSMCs indicate a marked heterogeneity of cGMP signaling pathways triggered by NO and natriuretic peptides, and that mechano-cGMP exists not only in platelets but also in many but not all VSMCs. The aim of this project is to identify the molecular mechanism and in vivo relevance of mechano-cGMP in VSMCs. We hypothesize that increased mechanical stress sensitizes NO-sensitive guanylyl cyclase (NO-GC) for activation by NO, so that dynamic cGMP signals are generated that depend on exposure of VSMCs to both NO and force. This could be an elegant mechanism to control vascular tone and blood flow. To test this hypothesis, we will visualize and modulate mechano-cGMP in murine and human VSMCs exposed to different types and levels of mechanical stress. The experiments will be performed in vitro with cultured cells, ex vivo with isolated blood vessels, and in vivo with wild-type and gene-mutated mice. We use a combination of biochemistry, proteomics, and high-resolution microscopy to study the molecular make-up of mechanosensitive cGMP signalosomes and whether they affect the contractile state, growth, and/or phenotype of VSMCs. Using FRET-based cGMP imaging and whole-organ 3D light-sheet microscopy performed in the Feil lab and Weigelin lab, respectively, we will test if cGMP-elevating drugs (e.g., NO-GC stimulators) can trigger mechano-cGMP in VSMCs and if this correlates with distinct anatomical niches. This study will provide novel insights into the signaling heterogeneity and mechano(patho)biology of the vessel wall and will inform new strategies to treat hypertension and other cardiovascular diseases.

• DFG Programme: Research Grants