Smooth muscle cell-specific Tgfbr1 deficiency promotes aortic aneurysm formation by stimulating multiple signaling events.

Transforming growth factor (TGF)-ß 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-ß signaling disorders in the aortic wall. In this study, we investigated the impact of deficiency of TGFß 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.

Preexisting smooth muscle cells contribute to neointimal cell repopulation at an incidence varying widely among individual lesions.

BACKGROUND: With the diverse origin of neointimal cells, previous studies have documented differences of neointimal cell lineage composition across models, but the animal-to-animal difference has not attracted much attention, although the cellular heterogeneity may impact neointimal growth and its response to therapeutic interventions. METHODS: R26R(+);Myh11-CreER(+), and R26R(+);Scl-CreER(+) mice were used to attach LacZ tags to the preexisting smooth muscle cells (SMCs) and endothelial cells (ECs), respectively. Neointimal lesions were created via complete ligation of the common carotid artery (CCA) and transluminal injury to the femoral artery (FA). RESULTS: LacZ-tagged SMCs were physically relocated from media to neointima and changed to a dedifferentiated phenotype in both CCA and FA lesions. The content of SMCs in the neointimal tissue, however, varied widely among specimens, ranging from 5 to 70% and 0 to 85%, with an average at low levels of 27% and 29% in CCA (n = 15) and FA (n = 15) lesions, respectively. Bone marrow cells, although able to home to the injured arteries, did not differentiate fully into SMCs after either type of injury. Preexisting ECs were located in the subendothelial region and produced mesenchymal marker α-actin, indicating endothelial-mesenchymal transition (EndoMT); however, EC-derived cells represented only 7% and 3% of the total neointimal cell pool of CCA (n = 7) and FA (n = 7) lesions, respectively. ECs located on the luminal surface exhibited little evidence of EndoMT. CONCLUSION: Neointimal hyperplasia proceeds with a wide range of variation in its cellular composition between individual lesions. Relative to ECs, SMCs are major contributors to the lesion-to-lesion heterogeneity in neointimal cell lineage composition.

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

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-ß signaling disorders. To understand the responsible mechanisms, we developed an animal model where inducible deletion of the type I TGF-ß receptor, Alk5, specifically in smooth muscle cells (Alk5iko) 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 Alk5iko males (n=42) developed aortic aneurysms and 26% of them died prematurely from aortic rupture. In contrast, the Alk5iko 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 Alk5iko 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 Alk5iko males. In conclusion, aortic aneurysm induced by Alk5iko 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.

Outcomes after redo aortobifemoral bypass for aortoiliac occlusive disease.

OBJECTIVE: Patients presenting with occluded aortobifemoral (ABF) bypass grafts are managed with a variety of techniques. Redo ABF (rABF) bypass procedures are infrequently performed because of concerns about procedural complexity and morbidity. The purpose of this analysis was to compare midterm results of rABF bypass with those of primary ABF (pABF) bypass for aortoiliac occlusive disease to determine if there are significant differences in outcomes. METHODS: A retrospective review was performed of all patients undergoing ABF bypass for occlusive disease between January 2002 and March 2012. A total of 19 patients underwent rABF bypass and 194 received pABF bypass during that period. Data for an indication- and comorbidity-matched case-control cohort of 19 elective pABF bypass patients were collected for comparison to the rABF bypass group. Primary end points included rate of major complications as well as 30-day and all-cause mortality. Secondary end points were amputation-free survival and freedom from major adverse limb events. RESULTS: The rABF bypass patients more frequently underwent prior extra-anatomic or lower extremity bypass operations compared with pABF bypass patients (P = .02); however, no difference was found in the incidence of prior failed endovascular iliac intervention (P = .4). By design, indications for the rABF and pABF bypass groups were the same (claudication, n = 6/6 [31.6%]; P = 1; critical limb ischemia, n = 13/13 [78.4%]; P = 1). Aortic access was more frequently by retroperitoneal exposure in the rABF bypass group (n = 13 vs n = 1; P < .0001), and a significantly higher proportion of the rABF bypass patients required concomitant infrainguinal bypass or intraprocedural adjuncts such as profundaplasty (n = 14 vs n = 5; P = .01). The rABF bypass patients experienced greater blood loss (1097 ± 983 mL vs 580 ± 457 mL; P = .02), received more intraoperative fluids (3400 ± 1422 mL vs 2279 ± 993 mL; P = .01), and had longer overall procedure times (408 ± 102 minutes vs 270 ± 48 minutes; P < .0001). Length of stay (days ± standard deviation) was similar (pABF bypass, 11.2 ± 10.4; rABF bypass, 9.1 ± 4.5; P = .7), and no 30-day or in-hospital deaths occurred in either group. Similar rates of major complications occurred in the two groups (pABF bypass, n = 6 [31.6%]; rABF bypass, n = 4 [21.1%]; observed difference, 9.5%; 95% confidence interval, -17.6% to 36.7%; P = .7). Two-year freedom from major adverse limb events (±standard error mean) was 82% ± 9% vs 78% ± 10% for pABF and rABF bypass patients (log-rank, P = .6). Two-year amputation-free survival was 90 ± 9% vs 89 ± 8% between pABF and rABF bypass patients (P = .5). Two-year survival was 91% ± 9% and 90% ± 9% for pABF and rABF bypass patients (P = .8). CONCLUSIONS: Patients undergoing rABF bypass have higher procedural complexity compared with pABF bypass as evidenced by greater operative time, blood loss, and need for adjunctive procedures. However, similar perioperative morbidity, mortality, and midterm survival occurred in comparison to pABF bypass patients. These results support a role for rABF bypass in selected patients.

Pediatric infiltration injury and compartment syndrome.

Pediatric intravenous infiltration injuries are relatively common, and pediatric compartment syndrome is relatively rare. We have reviewed the causes, means of diagnosis, and treatment of compartment syndrome. Neonatal compartment syndrome is distinguished from intravenous infiltration injuries in the neonate by its associated skin lesions and requires prompt decompression.