Chemogenetic Ca ²⁺ Channel Mitigates Aortic Dissection and Antihypertensive Risk

BACKGROUND: Thoracic aortic dissection (TAD) is a highly lethal disease without effective drug therapy. Guidelines recommend control of risk factors, particularly of causal hypertension. Antihypertensive drugs are diverse in mechanisms of action, but no randomized controlled trials have been undertaken to evaluate their efficacy and safety, and guide rational drug selection for this disease. METHODS: Antihypertensive drugs were evaluated in a 3-aminopropionitrile-induced mouse model of TAD. Pharmacovigilance analysis using the FDA Adverse Events Reporting System and Medical Information Mart for Intensive Care databases, along with a systematic meta-analysis of 32 studies, was performed to assess drug-associated risks in aortic diseases. Signaling pathways related to smooth muscle cell contractility, adhesion, and cytoskeleton stabilization were examined in human and mouse tissues. A chemogenetic mouse strain with smooth muscle cell-specific expression of the pharmacologically selective actuator module 4-serotonin type 3 receptor channel was generated to modulate Ca 2+ signaling. RESULTS: Here, we assessed 8 classes of antihypertensives in a mouse TAD disease model but unexpectedly observed that hydrochlorothiazide and minoxidil exacerbated the disease. Pharmacovigilance analysis linked diuretic use to an increased TAD-associated risk in patients. TAD pathogenesis and the harmful drug effects are attributable to blunted Ca 2+ -dependent smooth muscle cell contractility and adhesion. To this therapeutic end, we leveraged a chemogenetic Ca 2+ -permeable cation channel (pharmacologically selective actuator module 4-serotonin type 3 receptor) exclusively activated by the clinical drug varenicline. The humanized chemogenetic device boosted smooth muscle cell Ca 2+ signaling, potentiated the Ca 2+ -dependent cellular processes, and protected against TAD and the aggravated phenotype induced by hydrochlorothiazide/minoxidil. CONCLUSIONS: This study calls for pharmacovigilance of certain antihypertensives in TAD, and suggests that pharmacologically selective actuator module 4-serotonin type 3 receptor, as a viable means of tuning Ca 2+ signaling, holds translational potential for TAD therapy.