Abstract 10955: The Effects of Acute and Chronic Selective Phosphodiesterase 1 Inhibition in Associated Smooth Muscle Cell-Specific Aging Features

Abstract

Introduction: Aging-related vascular smooth muscle cell (VSMC) remodeling plays an essential role in cardiovascular diseases. Reduced NO-cGMP pathway signalling is a major feature and pathogenic mechanism underlying VSMC dysfunction. Recently, we found that phosphodiesterase (PDE) 1, an enzyme that hydrolyzes and inactivates the cyclic nucleotides cAMP and cGMP, is a potential treatment target for restoring age-related deficits in VSMC signalling. We here tested the effects of PDE1 inhibition in SMC-specific Ercc1 DNA repair mutant mice, a model of isolated, accelerated SMC aging. Design and Method: SM22α Cre+ Ercc1 fl/- (SMC-KO) and SM22α Cre+ Ercc1 fl/+ littermate (SMC-LM) mice receive either vehicle or the PDE1 inhibitor lenrispodun (dose 40mg/kg/day) in drinking water for 8 weeks. Reactive hyperemia was measured in-vivo at the age of 14 and 25 weeks. Mice were sacrificed at 26 weeks. The endothelium-dependent (ED) and -independent (EI) relaxation of the thoracic aorta was assessed by wire myography. Moreover, we investigated the effect of PDE1 inhibition on the expression of selected PDEs involved in the vasculature by qPCR. Results: Reactive hyperemia was dramatically reduced in vehicle-treated SMC-KO vs. SMC-LM at the age of 25 weeks (P=0.0002) but was preserved in lenrispodun-treated SMC-KO mice. In vehicle-treated SMC-KO mice, the ED and EI relaxations were greatly diminished compared to SMC-LM (ED: 23.92±4.34 vs. 68.04±4.86, P<0.0001; EI: 57.93±5.31 vs. 87.43±4.01, P=0.0004). Acute administration of lenrispodun in the organ bath improved both ED and EI responses (ED: 38.61±4.04, P=0.001; EI 69.99±4.29 P=0.01) while the relaxations remained unchanged after chronic lenrispodun treatment. In addition, lenrispodun upregulated PDE1a mRNA expression in SMC-KO, while no changes were observed in other PDEs. Conclusions: PDE1 inhibition may therapeutically be useful in restoring age-related vascular dysfunction by preserving microvascular function and potentiating NO-cGMP signaling. Yet, its chronic effects might be counteracted by the upregulation of PDE1a in vasculature. These results warrant further pharmacodynamic profiling of PDE enzyme regulation during chronic PDE1 inhibitor treatment.