Abstract 4338723: The role of Phosphodiesterase 1A in aortic aneurysm and dissection

Background: Aortic aneurysm and dissection (AAD) are life-threatening diseases characterized by progressive degradation of the aortic wall. The loss of contractile phenotype in vascular smooth muscle cells (SMCs) promotes AAD development. Phosphodiesterase 1A (PDE1A), predominantly expressed in contractile vascular SMCs, regulates vascular contractility; however, its role in AAD remains unclear. Methods: PDE1A and contractile gene expression was analyzed by published sequencing datasets, qPCR and immunostaining in human and mouse AAD tissues. The role of PDE1A in AAD was investigated using global PDE1A knockout (KO) mice and vascular SMC-specific PDE1A KO mice. Both high-fat diet with Angiotensin II infusion (HFD/Ang II) induced sporadic AAD, and elastase/BAPN-induced abdominal aortic aneurysm (AAA) model were used. Results: PDE1A expression in vascular SMCs was decreased in both human and mouse AAD. In the HFD/Ang II model, global PDE1A KO significantly lowered the incidence of aortic aneurysm, dissection, and rupture in both genders, which was confirmed in the elastase/BAPN model. PDE1A expression in the aortic media of AAD mice positively correlated with contractile marker gene expression (e.g., Myh11, Sm22, and Cnn1 ), a finding confirmed in human samples. Interestingly, PDE1A global KO mice under basal conditions showed reduced contractile gene expression in media, a result replicated in rat aortic SMCs with PDE1A knockdown, indicating PDE1A is a critical regulator of vascular SMC contractile gene expression. To define the role of vascular SMC-expressed PDE1A in AAD, we generated vascular SMC-specific PDE1A KO mice (PDE1A-KO VSMC ) using Itga8-CreER mice. PDE1A-KO VSMC mice also showed decreased expression of contractile markers in media. In contrast to the global PDE1A KO, PDE1A-KO VSMC mice aggravated aortic dilation and elastin degradation in the elastase/BAPN model. Since PDE1A expression was also detected in the adventitia and was upregulated in early stages of AAD, the potential role of adventitial fibroblast-expressed PDE1A in AAD pathogenesis is currently under investigation. Conclusion: Global deletion of PDE1A protects against AAD; whereas vascular SMC-specific deletion of PDE1A exacerbates AAD, possibly due to impaired vascular SMC contractile function. These findings highlight the essential role of PDE1A in vascular contractility and suggest a distinct role for PDE1A in adventitia fibroblasts in AAD.