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Vascular smooth muscle cells (VSMCs) derived from cardiovascular progenitor cell (CVPC) lineage populate the tunica media of the aortic root. Understanding differentiation of VSMCs from CVPC will further our understanding of the molecular mechanisms contributing to aortic root aneurysms, and thus, facilitate the development of novel therapeutic agents to prevent this devastating complication.
It is established that the yes-associated protein (YAP) and Hippo pathway is important for VSMC proliferation and phenotype switch. To determine the role of YAP in differentiation of VSMCs from CVPCs, we utilized the in vitro monolayer lineage specific differentiation method by differentiating human embryonic stem cells into CVPCs, and then, into VSMCs.
We found that expression of YAP decreased during differentiation of VSMC from CVPCs. Overexpression of YAP attenuated expression of VSMC contractile markers and impaired VSMC function. Knockdown of YAP increased expression of contractile proteins during CVPC-VSMCs differentiation. Importantly, expression of YAP decreased transcription of myocardin during this process. Overexpression of YAP in PAC1 SMC cell line inhibited luciferase activity of myocardin proximal promoter in a dose dependent and NKX2.5 dependent manner. YAP protein interacted with NKX2.5 protein and inhibited binding of NKX2.5 to the 5’-proximal promoter region of myocardin in CVPC-derived VSMCs.
In conclusion, YAP negatively regulates differentiation of VSMCs from CVPCs by decreasing transcription of myocardin in a NKX2.5-dependent manner.