V ascular smooth muscle cell (VSMC) activation and phenotypic switching are critical for remodeling processes in vascular proliferative disorders, including intimal hyperplasia. Both the migratory and proliferative activities of VSMCs, as well as the interplay between the extracellular matrix (ECM) and integrin receptors essentially, contribute to neointimal hyperplasia and restrictive remodeling processes in the vessels.1 Among integrins, the particular role of integrin α V β 3 in the induction of VSMC responses has been shown both in vivo and in vitro.
BackgroundSymptomatic peripheral artery disease (PAD) is an atherosclerotic occlusive disease affecting the lower extremities. The cause of symptomatic PAD is atherosclerosis, vascular dysfunctions, impaired angiogenesis and neointima formation. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein, which is highly expressed in the heart and arteries and recently introduced as a potential mediator of pathological vascular remodeling and neointima formation. We aimed to investigate the relationship between serum MFAP4 (sMFAP4) and symptomatic PAD outcomes.MethodsA total of 286 PAD patients were analyzed if they had either intermittent claudication or critical lower-extremity ischemia (CLI) and followed for 7 years. The level of serum MFAP4 (sMFAP4) was measured by alphaLISA. Kaplan–Meier, Cox proportional hazard and logistic regression analysis were used to analyze the associations between upper tertile sMFAP4 and symptomatic PAD outcomes.ResultsPatients with upper tertile sMFAP4 had an odds ratio (OR) of 2.65 (p < 0.001) for having CLI diagnosis. Further analysis indicated that patients with upper tertile sMFAP4 had a hazard ratio (HR) of 1.97 (p = 0.04) for cardiovascular death during the 7-years follow-up. However, analysis of 2-year primary patency showed that patients with upper tertile sMFAP4 had decreased risk of vascular occlusion after reconstructive surgery with HR of 0.15 (p = 0.02).ConclusionssMFAP4 has potential as a prognostic marker for cardiovascular death, primary patency of reconstructed vessels and CLI diagnosis in symptomatic PAD patients. Confirmation of observations in larger cohorts is warranted.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1523-6) contains supplementary material, which is available to authorized users.
Arterial injury stimulates remodeling responses that, when overexuberant, leads to stenosis. This response is influenced by specific integrin signaling in vascular smooth muscle cells (VSMCs). Microfibrillar-associated protein 4 (MFAP4) is a matricellular integrin ligand localized to the vascular wall. We hypothesized that systemic MFAP4 (sMFAP4) associates to vascular remodeling processes and that MFAP4 enhances integrin dependent VSMC activation and vasculoproliferative disease-associated remodeling. We explored the hypotheses using a prospective human cohort with symptomatic obstructive peripheral arterial disease (PAD), VSMC culture studies, and produced MFAP4 deficient mice for studying neointima formation. We demonstrate that the highest tertile of sMFAP4 was significantly associated with primary patency after vascular reconstruction, and the overall need for vascular reconstruction and mortality in 343 PAD patients. MFAP4 mediated the adhesion, migration, and proliferation of VSMCs in an integrin αVβ3/5-dependent manner in vitro. These effects were inhibited by MFAP4-blocking antibodies. MFAP4-deficient mice displayed delayed neointimal formation when challenged with carotid artery ligation, but the compensatory outward remodeling of vessel diameter was reduced. In conclusion, sMFAP4 has the potential to serve as a systemic marker morbidity and mortality in PAD. MFAP4 regulates integrin αVβ3/5 signaling and pathological remodeling in vivo, and may have therapeutic implications in vasculoproliferative diseases.
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