Phosphodiesterase 4 Regulates Intrinsic Cell Function And Participates In The Mechanism And Intervention Of Vascular Remodeling Disease

BackgroundVascular disease is one of the major global health problems and its main pathophysiological change is vascular remodelling.Vessel intrinsic cells—endothelial cells(EC)and smooth muscle cells(SMC)play important roles in the homeostasis maintenance of the structure and function of vessels as well as pathological remodelling.Cyclic adenosine monophosphate(cAMP)is a second messenger in cells,involving multiple signalling pathways closely related to vascular diseases.Phosphodiesterase(PDE)4 is a PDE subfamily that specifically hydrolyses cAMP,consisting of four subtypes(PDE4A,PDE4B,PDE4C,PDE4D),and has been proven to be an effective therapeutic target for many diseases,but the heterogeneous role of each isoform in vascular diseases and remodelling is not fully understood.AimsTaking two vascular diseases,pulmonary hypertension(PH)and hypertension,as examples,to explore the roles and underlying mechanisms of PDE4 subfamily members in cardiopulmonary and vascular diseases by focusing on the function of vascular intrinsic cells.Methods and ResultsPrevious studies in our lab found that PDE4B was up-regulated in PH lung tissues,and mainly expressed in pulmonary vascular EC.(1)By constructing PH models on conditional gene knockout mice and detecting pathologic phenotypes,we found that the PDE4B deficiency in EC can significantly ameliorate the PH in mice,and PDE4B is related to the proliferation of EC in the PH.(2)Through PDE4B knockdown and PDE4 inhibitor treatment experiments on mouse pulmonary artery endothelial cells(mPAEC)in vitro,we found that the loss of PDE4B or the inhibition of PDE4 in mPAEC can significantly inhibit the proliferation and migration induced by hypoxia.(3)By constructing PH models on rats and administering PDE4B inhibitors,we found that PDE4B-specific inhibition can significantly ameliorate the PH in rats.Previous studies in our lab also revealed that there was an increase in the expression of PDE4D in the aortas of hypertensive mice,and in vitro cell experiments demonstrated that PDE4D promoted SMC contraction.(1)After constructing hypertension models on conditional gene knockout mice and treating them with PDE4 inhibitors,by measuring mesenteric arteriole tension,we found that PDE4D deficiency in SMC or systemic PDE4 inhibition can significantly improve resistance vasoconstriction abnormalities in hypertensive mice.(2)By detecting the downstream signalling pathway of PDE4D,we found that PDE4D can promote the contraction of SMC through the PKA/AMPK-MYPT1/MLC signalling pathway,resulting in abnormal resistance vasoconstriction in hypertension.ConclusionWithin the PDE4 subfamily,PDE4B may contribute to the development of PH by promoting the proliferation and migration of EC,while PDE4D may contribute to hypertension by promoting abnormal constriction and relaxation of EC.Accordingly,the use of subtype-specific PDE4 inhibitors may hold promise as a potential treatment for vascular remodelling diseases.