Objective: Arterial restenosis is the pathological narrowing of arteries after endovascular procedures, and it is an adverse event that causes patients to experience recurrent occlusive symptoms. Following angioplasty, vascular smooth muscle cells (SMCs) change their phenotype, migrate, and proliferate, resulting in neointima formation, a hallmark of arterial restenosis. SIKs (salt-inducible kinases) are a subfamily of the AMP-activated protein kinase family that play a critical role in metabolic diseases including hepatic lipogenesis and glucose metabolism. Their role in vascular pathological remodeling, however, has not been explored. In this study, we aimed to understand the role and regulation of SIK3 in vascular SMC migration, proliferation, and neointima formation. Approach and Results: We observed that SIK3 expression was low in contractile aortic SMCs but high in proliferating SMCs. It was also highly induced by growth medium in vitro and in neointimal lesions in vivo. Inactivation of SIKs significantly attenuated vascular SMC proliferation and up-regulated p21 CIP1 and p27 KIP1 . SIK inhibition also suppressed SMC migration and modulated actin polymerization. Importantly, we found that inhibition of SIKs reduced neointima formation and vascular inflammation in a femoral artery wire injury model. In mechanistic studies, we demonstrated that inactivation of SIKs mainly suppressed SMC proliferation by down-regulating AKT (protein kinase B) and PKA (protein kinase A)-CREB (cAMP response element-binding protein) signaling. CRTC3 signaling likely contributed to SIK inactivation-mediated antiproliferative effects. Conclusions: These findings suggest that SIK3 may play a critical role in regulating SMC proliferation, migration, and arterial restenosis. This study provides insights into SIK inhibition as a potential therapeutic strategy for treating restenosis in patients with PAD.

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Background: Ischemic colitis after an open abdominal aortic aneurysm (AAA) repair remains a serious complication with a nationally reported rate of 1% to 6% in elective cases and up to 60% after an aneurysmal rupture. To prevent this serious complication, inferior mesenteric artery (IMA) replantation is performed at the discretion of the surgeon based on his or her intraoperative findings, despite the lack of clear evidence to support this practice. The purpose of this study was to determine whether replantation of the IMA reduces the risk of ischemic colitis and improves the overall outcome of AAA repair. Methods:Patients who underwent open infrarenal AAA repair were identified in the multicenter American College of Surgeons National Surgical Quality Improvement Program Targeted AAA Database from 2012 to 2015. Emergency cases, patients with chronically occluded IMAs, ruptured aneurysms with evidence of hypotension, and patients requiring visceral revascularization were excluded. The remaining elective cases were divided into two groups: those with IMA replantation (IMA-R) and those with IMA ligation. We measured the 30-day outcomes including mortality, morbidity, and perioperative outcomes. A multivariable logistic regression model was used for data analysis, adjusting for clinically relevant covariates.Results: We identified 2397 patients who underwent AAA repair between 2012 and 2015, of which 135 patients (5.6%) had ischemic colitis. After applying the appropriate exclusion criteria, there were 672 patients who were included in our study. This cohort was divided into two groups: 35 patients with IMA-R and 637 patients with IMA ligation. There were no major differences in preoperative comorbidities between the two groups. IMA-R was associated with increased mean operative time (319.7 6 117.8 minutes vs 242.4 6 109.3 minutes; P < .001). Examination of 30-day outcomes revealed patients with IMA-R had a higher rate of return to the operating room (20.0% vs 7.2%; P ¼ .006), a higher rate of wound complications (17.1% vs 3.0%; P ¼ .001), and a higher incidence of ischemic colitis (8.6% vs 2.4%; P ¼ .027). There were no significant differences in mortality, pulmonary complications, or renal complications between the two groups. In multivariable analysis, IMA-R was a significant predictor of ischemic colitis and wound complications.Conclusions: These data suggest that IMA-R is not associated with protection from ischemic colitis after open AAA repair. The role of IMA-R remains to be identified.