AUTHOR=Golshiri Keivan , Ataabadi Ehsan Ataei , Jüttner Annika A. , Snyder Gretchen L. , Davis Robert E , Lin Amy , Zhang Lei , de Vries René , Garrelds Ingrid M , Leijten Frank P. J. , Danser A. H. Jan , Roks Anton J. M. 

TITLE=The Effects of Acute and Chronic Selective Phosphodiesterase 1 Inhibition on Smooth Muscle Cell-Associated Aging Features

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.818355

DOI=10.3389/fphar.2021.818355

ISSN=1663-9812

ABSTRACT=<p>Age-related cardiovascular diseases (CVDs) remain among the leading global causes of death, and vascular smooth muscle cell (VSMC) remodeling plays an essential role in its pathology. Reduced NO-cGMP pathway signaling is a major feature and pathogenic mechanism underlying vasodilator dysfunction. Recently, we identified phosphodiesterase (PDE) 1, an enzyme that hydrolyzes and inactivates the cyclic nucleotides <ext-link ext-link-type="uri" xlink:href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2352" xmlns:xlink="http://www.w3.org/1999/xlink">cAMP</ext-link> and <ext-link ext-link-type="uri" xlink:href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2347" xmlns:xlink="http://www.w3.org/1999/xlink">cGMP</ext-link>, and thereby provides a potential treatment target for restoring age-related vascular dysfunction due to aging of VSMC. Based on this hypothesis, we here tested the effects of PDE1 inhibition in a model of SMC-specific accelerated aging mice. SMC-KO and their WT littermates received either vehicle or the PDE1 inhibitor lenrispodun for 8 weeks. Vascular function was measured both <italic>in vivo</italic> (Laser Doppler technique) and <italic>ex vivo</italic> (organ bath). Moreover, we deployed UV irradiation in cell culture experiments to model accelerated aging in an <italic>in vitro</italic> situation. SMC-KO mice display a pronounced loss of vasodilator function in the isolated aorta, the cutaneous microvasculature, and mesenteric arteries. <italic>Ex vivo</italic>, in isolated vascular tissue, we found that PDE1 inhibition with lenrispodun improves vasodilation, while no improvement was observed in isolated aorta taken from mice after chronic treatment <italic>in vivo</italic>. However, during lenrispodun treatment <italic>in vivo</italic>, an enhanced microvascular response in association with upregulated cGMP levels was seen. Further, chronic lenrispodun treatment decreased TNF-α and IL-10 plasma levels while the elevated level of IL-6 in SMC-KO mice remained unchanged after treatment. PDE1 and senescence markers, <italic>p16</italic> and <italic>p21</italic>, were increased in both SMC-KO aorta and cultured human VSMC in which DNA was damaged by ultraviolet irradiation. This increase was lowered by chronic lenrispodun. In contrast, lenrispodun increased the level of PDE1A in both situations. In conclusion, we demonstrated that PDE1 inhibition may be therapeutically useful in reversing aspects of age-related VSMC dysfunction by potentiating NO-cGMP signaling, preserving microvascular function, and decreasing senescence. Yet, after chronic treatment, the effects of PDE1 inhibition might be counteracted by the interplay between differential PDE1A and C expression. These results warrant further pharmacodynamic profiling of PDE enzyme regulation during chronic PDE1 inhibitor treatment.</p>