SUN2 accumulation contributes to vascular smooth muscle cell alterations induced by matrix rigidity

Abstract

In the vascular system, arterial wall cell phenotype and fate are driven by the mechanical properties of their surrounding environment. Changes in the mechanical environment, such as age‐related extracellular matrix (ECM) stiffening, alter vascular cell phenotype and growth, leading to inflammation and vascular remodeling, which favor cardiovascular diseases. Despite recent advances, how mechanical cues regulate cell phenotype remains poorly understood. By combining proteomic and biophysical assays, we recently identified nuclear proteins whose expression or post translational modifications are regulated by matrix rigidity. Among the identified candidates is Sad1/UNC‐84 domain‐containing protein 2 (SUN2), which belongs to the linker of nucleoskeleton and cytoskeleton complex and enables mechanical force transmission from the cytoskeleton to the nucleus. We observed increased SUN2 expression in vascular smooth muscle cells (VSMCs) cultured on rigid matrix. Interestingly, we found that SUN2 depletion prevented the increase in cell proliferation in response to matrix rigidity. Using a mouse model of endothelial injury, we observed SUN2 accumulation in the neointima at sites of cell proliferation. To analyze VSMC contractile function we used atomic force microscopy (AFM). We found that SUN2 depletion decreased VSMC contractile response to AFM pulling forces. All together these results indicate that upregulation of SUN2 contributes to the increased proliferation and altered contractility of VSCM in response to matrix stiffening.