Transforming growth factor (TGF)-β signaling disorder has emerged as a common molecular signature for aortic aneurysm development. The timing of postnatal maturation plays a key role in dictating the biological outcome of TGF-β signaling disorders in the aortic wall. In this study, we investigated the impact of deficiency of TGFβ receptors on the structural homeostasis of mature aortas. We used an inducible Cre-loxP system driven by a Myh11 promoter to delete Tgfbr1, Tgfbr2, or both in smooth muscle cells (SMCs) of adult mice. TGFBR1 deficiency resulted in rapid and severe aneurysmal degeneration, with 100% penetrance of ascending thoracic aortas, whereas TGFBR2 deletion only caused mild aortic pathology with low (26%) lesion prevalence. Removal of TGFBR2 attenuated the aortic pathology caused by TGFBR1 deletion and correlated with a reduction of early ERK phosphorylation. In addition, the production of angiotensin (Ang)-converting enzyme was upregulated in TGFBR1 deficient aortas at the early stage of aneurysmal degeneration. Inhibition of ERK phosphorylation or blockade of AngII type I receptor AT1R prevented aneurysmal degeneration of TGFBR1 deficient aortas. In conclusion, loss of SMC-Tgfbr1 triggers multiple deleterious pathways, including abnormal TGFBR2, ERK, and AngII/AT1R signals that disrupt aortic wall homeostasis to cause aortic aneurysm formation.

Objective Spinal cord ischemia(SCI) is a potentially devastating complication of thoracic endovascular aortic repair(TEVAR) that can result in varying degrees of short-term and permanent disability. This study was undertaken to describe the clinical outcomes, long-term functional impact, and influence on survival of SCI after TEVAR. Methods A retrospective review of all TEVAR patients at the University of Florida from 2000–2011 was performed to identify individuals experiencing SCI as defined by any new lower extremity neurologic deficit not attributable to another cause. SCI was dichotomized into immediate or delayed onset, with immediate onset defined as SCI noted upon awakening from anesthesia, and delayed characterized as a period of normal function followed by development of neurologic injury. Ambulatory status was determined using database query, chart review and phone interviews with patients and/or family. Mortality was estimated using life-tables. Results 607 TEVARs were performed for various indications, with 57 patients(9.4%) noted to have postoperative SCI(4.3% permanent). SCI patients were more likely to be older (63.9±15.6 vs. 70.5±11.2;p=.002) and have a number of comorbidities including: COPD, hypertension, dyslipidemia and cerebrovascular disease(P<.0001). Fifty-four patients(95%) had a CSF drain placed at some point in their care, with the majority placed postoperatively(54%). In-hospital mortality was 8.8% for the entire cohort(SCI vs. No SCI;P=.45). Twelve patients developed immediate SCI, 40 had delayed onset, and 5 were indeterminate due to indiscriminate timing from postoperative sedation. Three(25%) immediate SCI patients had measurable functional improvement (FI), while 28(70%) of the delayed-onset patients experienced some degree of neurologic recovery(P=.04). Of the 34 patients with complete data available, 26(76%) reported quantifiable FI, while only 13(38%) experienced return to preoperative baseline. Estimated mean survival(±standard error) for patients with and without SCI was 37.2±4.5 and 71.6±3.9 months(P<.0006), respectively. Patients with FI had a mean survival of 53.9±5.9 months compared to 9.6±3.6 months for those without improvement(P<.0001). Survival and return of neurologic function were not significantly different when comparing patients with pre- and postoperative CSF drains. Conclusions The minority of patients experience complete return to baseline function after suffering SCI with TEVAR, and outcomes in patients without early functional recovery are particularly dismal. Patients experiencing delayed SCI are more likely to have FI and may anticipate similar life-expectancy with neurologic recovery compared to patients without SCI. Timing of drain placement does not appear to have an impact on post-discharge FI or long-term mortality.

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.