{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:19:36Z","timestamp":1790255976104,"version":"4.1.0"},"reference-count":46,"publisher":"American Physiological Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2015,1,15]]},"abstract":"<jats:p> The prevalence of aortic aneurysm is five times higher in men than women among the general population. Similar sexual dimorphism also exists in syndromic aortic aneurysms triggered by TGF-\u03b2 signaling disorders. To understand the responsible mechanisms, we developed an animal model where inducible deletion of the type I TGF-\u03b2 receptor, Alk5, specifically in smooth muscle cells ( Alk5<jats:sup> iko<\/jats:sup>) causes spontaneous aortic aneurysm formation. This model recapitulated an extreme scenario of the dimorphism in aortic aneurysm development between genders. In a comparative experiment, all Alk5<jats:sup> iko<\/jats:sup> males ( n = 42) developed aortic aneurysms and 26% of them died prematurely from aortic rupture. In contrast, the Alk5<jats:sup> iko<\/jats:sup> females ( n = 14) presented only a subclinical phenotype characteristic of scarcely scattered elastin breaks. Removal of male hormones via orchiectomy ( n = 7) resulted in only minimal influence on aortic pathology. However, reduction of female hormones via ovariectomy ( n = 15) increased the phenotypic penetrance from zero to 53%. Finally, an elevation of systolic blood pressure by 30 points unmasked the subclinical phenotype of Alk5<jats:sup> iko<\/jats:sup> females ( n = 17) to 59%. This exaggerated phenotypic penetrance was coupled with an early intensification of ERK signaling, a molecular signature that correlated to 100% phenotypic penetrance in normotensive Alk5<jats:sup> iko<\/jats:sup> males. In conclusion, aortic aneurysm induced by Alk5<jats:sup> iko<\/jats:sup> exhibits dimorphic incidence between genders with females less susceptible to aortic disease. This sexual dimorphism is partially the result from the protective effects of female hormones. Hypertension, a known risk factor for aortic aneurysm, is able to break the female sex protective effects through mechanisms associated with enhanced ERK activity. <\/jats:p>","DOI":"10.1152\/ajpheart.00521.2014","type":"journal-article","created":{"date-parts":[[2014,11,15]],"date-time":"2014-11-15T05:27:15Z","timestamp":1416029235000},"page":"H115-H125","source":"Crossref","is-referenced-by-count":26,"title":["Hypertension overrides the protective effect of female hormones on the development of aortic aneurysm secondary to Alk5 deficiency via ERK activation"],"prefix":"10.1152","volume":"308","author":[{"given":"Bradley M.","family":"Schmit","sequence":"first","affiliation":[{"name":"Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, Florida; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pu","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, Florida; 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