Soluble adenylyl cyclase (sAC) regulates calcium signaling in the vascular endothelium

The vascular endothelium acts as a selective barrier between the bloodstream and extravascular tissues. Intracellular [Ca 2+ ] i signaling is essential for vasoactive agonist‐induced stimulation of endothelial cells (ECs), typically including Ca 2+ release from the endoplasmic reticulum (ER). Although it is known that interactions of Ca 2+ and cAMP as ubiquitous messengers are involved in this process, the individual contribution of cAMP‐generating adenylyl cyclases (ACs), including the only soluble AC (sAC; ADCY10), remains less clear. Using life‐cell microscopy and plate reader‐based [Ca 2+ ]i measurements, we found that human immortalized ECs, primary aortic and cardiac microvascular ECs, and primary vascular smooth muscle cells treated with sAC‐specific inhibitor KH7 or anti‐sAC‐small interfering RNA did not show endogenous or exogenous ATP‐induced [Ca 2+ ]i elevation. Of note, a transmembrane AC (tmAC) inhibitor did not prevent ATP‐induced [Ca 2+ ] i elevation in ECs. Moreover, l ‐phenylephrine‐dependent constriction of ex vivo mouse aortic ring segments was also reduced by KH7. Analysis of the inositol‐1,4,5‐trisphosphate (IP 3 ) pathway revealed reduced IP 3 receptor phosphorylation after KH7 application, which also prevented [Ca 2+ ] i elevation induced by IP 3 receptor agonist adenophostin A. Our results suggest that sAC rather than tmAC controls the agonist‐induced ER‐dependent Ca 2+ response in ECs and may represent a treatment target in arterial hypertension and heart failure.—Mewes, M., Lenders, M., Stappers, F., Scharnetzki, D., Nedele, J., Fels, J., Wedlich‐Söldner, R., Brand, S.‐M., Schmitz, B., Brand, E. Soluble adenylyl cyclase (sAC) regulates calcium signaling in the vascular endothelium. FASEB J. 33, 13762‐13774 (2019). www.fasebj.org