Abstract
INTRO: Hypertension and gender are established risk factors for aortic aneurysm (AA) development, yet recent evidence suggests that alterations in TGF-beta signaling is one of the key initiators of AA. We have previously shown that loss of the Alk5 TGF-B type 1 receptor in male but not female mice leads to AA (100% penetrance). Here, we explore the interaction of gender, biomechanical forces, and TGF-B biology. We hypothesize that the female Alk-5 deficient mice are a subclinical phenotype that can be unmasked by the biologic alterations that accompany systemic hypertension. METHODS: SMC specific Alk5 deletion (Alk5-/-) was achieved via an inducible Cre-loxP system. Wild-type (Alk5f/f) and Alk5-/- females received continuous infusion of Norepinephrine (NE) to increase blood pressure. Non-infused Alk5f/f and Alk5-/- females were included as controls. Aortic pathology was examined grossly and histologically at 4 wks. Production of p-Erk, an index for activation of the non-canonical TGF-B signaling pathway, was quantified on aortic tissue before and after 2wks of treatment. RESULTS: NE elevated SBP in both groups by 35 mmHg. The combination of Alk5-/- and HTN (Alk5-/-/HTN) in female mice increased the penetrance of AA from zero to 57% (p< .05). In contrast, no pathology was detected in the wild-type/HTN or ALK5-/- mice, where animals were only affected by a single factor. Alk5-/-/HTN aortas showed significant upregulation (2.1x, p<.05) of pErk, while a single factor, either Alk5-/- or HTN, was unable to enhance early Erk signaling in affected aortic tissue. CONCLUSION: Hypertension breaks the sex-protective effects on AA formation induced by SMC specific Alk5 deletion in females. The combination of hypertension and Alk5 deficiency is required to intensify an early Erk signaling and subsequently induce aortic pathology. This strong association suggests Erk serves as the biological mediator for hemodynamic stress modulated sexual dimorphism during AA development.
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