Vascular smooth muscle cells exhibit varied responses after vessel injury and surgical interventions, including phenotypic switching, migration, proliferation, protein synthesis, and apoptosis. Although the source of the smooth muscle cells that accumulate in the vascular wall is controversial, possibly reflecting migration from the adventitia, from the circulating blood, or in situ differentiation, the intracellular signal transduction pathways that control these processes are being defined. Some of these pathways include the Ras-mitogen-activated protein kinase, phosphatidylinositol 3-kinase-Akt, Rho, death receptor-caspase, and nitric oxide pathways. Signal transduction pathways provide amplification, redundancy, and control points within the cell and culminate in biologic responses. We review some of the signaling pathways activated within smooth muscle cells that contribute to smooth muscle cell heterogeneity and development of pathology such as restenosis and neointimal hyperplasia.

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Orbital shear stress directly stimulates SMC proliferation in long-term culture in vitro and is mediated, at least partially, by the ERK1/2 pathway. The ERK1/2 pathway may also mediate the orbital shear-stress-stimulated switch from SMC contractile to synthetic phenotype. These results suggest that shear-stress-stimulated SMC proliferation after vascular injury is mediated by a pathway amenable to pharmacologic manipulation.

Vascular smooth muscle cells (SMC) may be directly exposed to blood flow after an endothelial-denuding injury. It is not known whether direct exposure of SMC to shear stress reduces SMC turnover and contributes to the low rate of restenosis after most vascular interventions. This study examines if laminar shear stress inhibits SMC proliferation or stimulates apoptosis. Bovine aortic SMC were exposed to arterial magnitudes of laminar shear stress (11 dynes/cm(2)) for up to 24 h and compared to control SMC (0 dynes/cm(2)). SMC density was assessed by cell counting, DNA synthesis by (3)[H]-thymidine incorporation, and apoptosis by TUNEL staining. Akt, caspase, bax, and bcl-2 phosphorylation were assessed by Western blotting; caspase activity was also measured with an in vitro assay. Analysis of variance was used to compare groups. SMC exposed to laminar shear stress had a 38% decrease in cell number (n = 4, P = 0.03), 54% reduction in (3)[H]-thymidine incorporation (n = 3, P = 0.003), and 15-fold increase in TUNEL staining (n = 4, P < 0.0001). Akt phosphorylation was reduced by 67% (n = 3, P < 0.0001), whereas bax/bcl-2 phosphorylation was increased by 1.8-fold (n = 3, P = 0.01). Caspase-3 activity was increased threefold (n = 5, P = 0.03). Pretreatment of cells with ZVAD-fmk or wortmannin resulted in 42% increased cell retention (n = 3, P < 0.01) and a fourfold increase in apoptosis (n = 3, P < 0.04), respectively. Cells transduced with constitutively-active Akt had twofold decreased apoptosis (n = 3, P < 0.002). SMC exposed to laminar shear stress have decreased proliferation and increased apoptosis, mediated by the Akt pathway. These results suggest that augmentation of SMC apoptosis may be an alternative strategy to inhibit restenosis after vascular injury.

Background: In the setting of Per ipheral Arter ial Disease (PAD), pedal arch interrogation by ultrasound has not been well described. Patients with noncompressible vessels and/or open wounds of the foot may preclude the use of ankle-brachial indices, toe pressure measurements, or TcPO2, respectively. We propose that pedal artery interrogations with Pedal Acceleration Time (PAT) can be a predictor for limb salvage in patients with Chronic Limb-Threatening Ischemia (CLTI). Methods: A retrospective review of a prospectively kept database was performed from 2018 to 2019. Patients with pending amputation due to severe infection (WIFI infection class 2 and 3) were excluded from the study. We identified 73 limbs with CLTI that fit the inclusion cr iter ia. Data included WIFI classification, age, gender, cardiovascular risk factors, PAT, ABI, and TBI when reliable, were collected. PAT measurements were categorized into 4 classifications; 1 (40-120 msec), 2 (121-180 msec), 3 (181-224 msec), and 4 (Greater than 225 msec). Statistical analyses were performed. Results: Seventy-three limbs with CLTI were included in our study. All patients underwent arterial revascularization with either percutaneous technique or arterial bypass. Limb salvage was achieved in 59 (81%) of the 73 limbs. All 59 limbs had a 2-classification improvement in their PAT following interventions. A total of 14 (19%) limbs without improvement in their PAT underwent above ankle level amputations. An improvement in PAT classes to class 1 or 2 is associated with limb salvage. Conclusions: Patients with noncompressible ankle pressures or nonobtainable toe pressures poses a challenge in the complete assessment of WIFI classification. Our group has shown that PAT can be used in the scoring system for severity of ischemia in conjunction with current WIFI classification. Our data suggests that limb salvage correlates with post procedure PAT in category 1 and 2. Therefore we propose that PAT be added as part of the WIFI classification.

Both neointimal hyperplasia and inward remodeling contribute to restenosis and lumen loss. Nogo-B has been recently described as an inhibitor of vascular injury and neointimal hyperplasia. To determine whether Nogo-B expression may be a mediator of inward remodeling, we examine the localization of expression of Nogo-B in an in vivo model that examines both neointimal hyperplasia and inward remodeling. The rabbit carotid artery was subjected to balloon injury, outflow branch ligation to reduce flow, or both balloon injury and reduction in flow. In balloon injury-induced neointimal hyperplasia Nogo-B expression was reduced in the intima and media but stimulated in the adventitia. In low flow-induced inward remodeling medial Nogo-B expression was not reduced and adventitial Nogo-B expression was not stimulated. Low flow significantly augmented balloon injury-induced neointimal hyperplasia and was accompanied by reduced intimal and medial Nogo-B expression, and increased adventitial Nogo-B expression in both smooth muscle cells and macrophages. Low flow-induced inward remodeling is not associated with changes in medial Nogo-B expression and is distinct from injury-induced neointimal hyperplasia. Pharmacological strategies to inhibit neointimal hyperplasia and restenosis using normal flow models may only partially account for lumen loss and therefore may not accurately predict responses in patients with extensive outflow disease.

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The lack of reporting guidelines coupled with a paucity of follow-up data weakens any recommendation regarding the optimal choice of intervention. To address these deficiencies, we recommend reporting guidelines specific to the trauma population that will allow better risk adjustment and improve the quality of the evidence base.