Hypertension overrides the protective effect of female hormones on the development of aortic aneurysm secondary to Alk5 deficiency via ERK activation

Abstract

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-β signaling disorders. To understand the responsible mechanisms, we developed an animal model where inducible deletion of the type I TGF-β receptor, Alk5, specifically in smooth muscle cells ( Alk5 iko) 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 iko males ( n = 42) developed aortic aneurysms and 26% of them died prematurely from aortic rupture. In contrast, the Alk5 iko 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 iko 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 iko males. In conclusion, aortic aneurysm induced by Alk5 iko 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.

An X‐linked Myh11‐CreERT2 mouse line resulting from Y to X chromosome‐translocation of the Cre allele

“…As aforementioned, the mice enrolled in the current study also carried an R26R reporter and were homozygous for the floxed Tgfbr1 allele. We have previously shown that acute loss of SMC Tgfbr1 causes thoracic aortic aneurysms and dissections (Schmit et al, ; Yang et al, b). These genetic modifications allowed us to evaluate the Cre activity in arterial SMCs.…”

“…We treated homozygous ( n = 3) and heterozygous ( n = 4) female mice with five consecutive doses of tamoxifen and collected the aortas 13 days after the first doses of tamoxifen injection. Evans Blue was injected intravenously 30 min prior to tissue collection to assist visualization of early stage aortopathy (Schmit et al, ; Yang et al, b). Consistent with the evaluation at d5 and d5/5, X‐gal staining of X/X Cre+ ATAs remained mosaic (53%) in medial SMCs at d13.…”

“…Several lines of inducible Cre drivers have been made available to target SMCs by placing the CreER T2 ‐expressing cassette under the promoter of Acta2 (Wendling et al, ), Tagln (Kuhbandner et al, ), or Myh11 (Wirth et al, ). Among these various Cre lines, the Myh11‐CreER T2 strain has gained an increasing application because of its ability to induce recombination of the floxed genes in SMCs at a high specificity and efficiency (Hu et al, ; Li et al, ; Schmit et al, ; Shankman et al, ). We have previously reported that the Cre activity of this mouse line is restricted to medial SMCs, and it drives successful recombination in aortas and peripheral muscular arteries at efficiency rate greater than 90% (Yang et al, ,b).…”

“…Our group has used the Myh11‐CreER + mouse line to study the role of SMCs in the pathogenesis of neointimal hyperplasia and aortic aneurysm development (Schmit et al, ; Yang et al, ,b). During the genotype screening process, we identified female carriers of the Cre allele and observed a stable inheritance of the Cre allele by both male and female offspring.…”

A Dab2Ip Genotype: Sex Interaction is Associated with Abdominal Aortic Aneurysm Expansion

“…Higher PP increases shear stress and aortic wall stress, thereby increasing risk for aneurysm expansion,49 likely mediated through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kβ) and mitogen-activated protein kinase (MAPK) pathways50—pathways that underlie cell survival/apoptosis and are regulated by DAB2IP. 51 Previous studies found significant apoptosis in the stiffened aortic segment located within AAA52 and a greater impact of activation of MAPK pathway on aneurysm expansion in hypertensive female versus male mice 53. Aortic wall tension54 and rupture rates of AAA2 are greater in women than men.…”