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Summary: Smooth muscle cell (SMC) accumulation is central to the pathogenesis of elastin-defective arterial diseases, including supravalvular aortic stenosis (SVAS). We previously demonstrated that elastin insufficiency activates Notch signaling in aortic SMCs. Activation of Notch is catalyzed by the enzyme gamma-secretase, but the role of catalytic subunits presenilin (PSEN)-1 or PSEN-2 in elastin aortopathy is not defined. Genetic approaches reveal that endothelial cell-specific Psen1 deletion does not improve elastin aortopathy whereas the deletion of either Psen1 in SMCs or Psen2 globally attenuates Notch pathway and SMC proliferation, mitigating aortic disease. With SMC-specific Psen1 deletion in elastin nulls, these rescue effects are more robust and in fact, survival is increased. SMC deletion of Psen1 also attenuates hypermuscularization in newborns heterozygous for the elastin null gene, which genetically mimics SVAS. Similarly, the pharmacological inhibition of PSEN-1 mitigates SMC accumulation in elastin aortopathy. These findings put forth SMC PSEN-1 as a potential therapeutic target in SVAS.

ABSTRACT: Background: Erectile dysfunction (ED) is a multifactorial disorder with both psychogenic and organic components, but psychosocial factors are usually neglected. Objective: The purpose of this study was to develop a smartphone application targeting psychosocial factors of ED and to examine its feasibility, acceptability, and treatment response to determine the parameters for a larger clinical trial. Methods: In this single-arm feasibility study, 8 participants with situational ED were enrolled. Dr. App, a newly developed smartphone treatment application for patients with psychogenic ED consisting of 8 weekly modules based on Acceptance and Commitment Therapy, was delivered. The primary outcome was comparison of the International Index of Erectile Function-15 domain scores measured pre- and post-intervention. Results: Six out of 8 participants completed the Dr. App and the post-intervention measures. The Wilcoxon signed-rank test showed a significant change in erectile function (P < 0.05; r = –0.65) and a significant trend in intercourse satisfaction (P < 0.10; r = –0.47) and overall satisfaction (P < .10; r = –0.47). Additionally, the reliable change index values were used to calculate the number of participants for whom a clinically meaningful difference occurred. The results showed that 33.30% of the participants had clinically meaningful differences in erectile function and 66.70% in intercourse satisfaction and overall satisfaction. On the other hand, no significant differences were shown in orgasmic function and sexual desire. Conclusions: Findings from this study support the feasibility, acceptability, and potential usefulness of the smartphone application targeting psychosocial factors of ED and warrant a larger randomized clinical trial to confirm the results.