ELUCIDATING LOCAL PHOSPHODIESTERASE 3A SIGNALING AS A BASIS FOR GAINING INSIGHT INTO HYPERTENSION-DRIVING MECHANISMS

Abstract

Objective: Mutant PDE3A causes hypertension by driving mechanisms that increase peripheral vascular resistance. However, the media to lumen ratio of vessels in mutant PDE3A rat models varied between second-order mesenteric arteries and thoracic aorta. This observation may be related to alterations of the mutant PDE3A in its intracellular location, its hyperactivity and aberrant phosphorylation, which could lead to altered compartmentalized cAMP signaling. PDE3A hydrolyzes cAMP. Therefore, we hypothesized that alterations in compartmentalized cAMP signaling in vascular smooth muscle cells (VSMC) contributes to the hypertension. Design and method: Three different VSMC models were established: VSMCs from rat thoracic aorta, VSMCs from rat secondary mesenteric arteries and VSMCs expressing mutant PDE3A that were differentiated from human induced pluripotent stem cells. The expression levels of PDE3A and candidate genes were detected by immunofluorescence microscopy, Western blotting and qPCR based on results of RNA sequencing. cAMP and Ca2+ signaling pathways are being evaluated by FRET technology and Ca2+ imaging. Results: VSMCs differentiated from human induced pluripotent stem cells could detect abundant expression of vascular smooth muscle cell markers. Differential expression levels of PDE3A and the two screened candidate genes were found in different types of VSMCs. Conclusions: Elucidating differences in cAMP and Ca2+ cycling between different types of VSMCs yielded new insight into the mechanisms of hypertension. The mutant PDE3A signaling may be a starting point for an innovative, PDE3A compartment-specific pharmacological concept for the treatment of hypertension.