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.

Pulmonary surfactant protein D (SP-D) is a host defence lectin of the innate immune system that enhances clearance of pathogens and modulates inflammatory responses. Recently it has been found that systemic SP-D is associated with metabolic disturbances and that SP-D deficient mice are mildly obese. However, the mechanism behind SP-D's role in energy metabolism is not known.Here we report that SP-D deficient mice had significantly higher ad libitum energy intake compared to wild-type mice and unchanged energy expenditure. This resulted in accumulation but also redistribution of fat tissue. Blood pressure was unchanged. The change in energy intake was unrelated to the basal levels of hypothalamic Pro-opiomelanocortin (POMC) and Agouti-related peptide (AgRP) gene expression. Neither short time systemic, nor intracereberoventricular SP-D treatment altered the hypothalamic signalling or body weight accumulation.In ad libitum fed animals, serum leptin, insulin, and glucose were significantly increased in mice deficient in SP-D, and indicative of insulin resistance. However, restricted diets eliminated all metabolic differences except the distribution of body fat. SP-D deficiency was further associated with elevated levels of systemic bacterial lipopolysaccharide.In conclusion, our findings suggest that lack of SP-D mediates modulation of food intake not directly involving hypothalamic regulatory pathways. The resulting accumulation of adipose tissue was associated with insulin resistance. The data suggest SP-D as a regulator of energy intake and body composition and an inhibitor of metabolic endotoxemia. SP-D may play a causal role at the crossroads of inflammation, obesity, and insulin resistance.

Objective: Identifying biomarkers for abdominal aortic aneurysms (AAA) could prove beneficial in prognosis of AAA and thus the selection for treatment. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein that is highly expressed in aorta. MFAP4 is involved in several tissue remodeling-related diseases. We aimed to investigate the potential role of plasma MFAP4 (pMFAP4) as a biomarker of AAA. Methods: Plasma samples and data were obtained for 504 male AAA patients and 188 controls in the Viborg Vascular (VIVA) screening trial. The pMFAP4 levels were measured by Alphalisa. The Mann-Whitney U test assessed differences in pMFAP4 levels between the presence and absence of different exposures of interest. The correlation between pMFAP4 and aorta growth rate were investigated through spearman's correlation analysis. Immunohistochemistry and multiple logistic regression adjusted for potential confounders assessed the association between pMFAP4 and AAA. Multiple linear regression assessed the correlation between pMFAP4 and aorta growth rate. Cox regression and competing risk regression were used to investigate the correlation between AAA patients with upper tertile pMFAP4 and the risk of undergoing later surgical repair. Results: A significant negative correlation between pMFAP4 and aorta growth rate was observed using spearman's correlation analysis (r ¼ À0.14; P ¼ .0074). However, this finding did not reach significance when applying multiple linear regression. A tendency of decreased pMFAP4 was observed in AAA using immunohistochemistry. Competing risk regression adjusted for potential confounders indicated that patients with upper tertile pMFAP4 had a hazard ratio of 0.51 (P ¼ .001) for risk of undergoing later surgical repair. Conclusions: High levels of pMFAP4 are associated with a decreased likelihood of receiving surgical repair in AAA. This observation warrants confirmation in an independent cohort.

Objective: Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix (ECM) protein involved in the induction of vascular remodeling. This study aimed to investigate if MFAP4 facilitates the development of AAA and characterize the underlying MFAP4-mediated mechanisms.Approach and Results: Double apolipoprotein E- and Mfap4-deficient (ApoE−/−Mfap4−/−) and control apolipoprotein E-deficient (ApoE−/−) mice were infused subcutaneously with angiotensin II (Ang II) for 28 days. Mfap4 expression was localized within the adventitial and medial layers and was upregulated after Ang II treatment. While Ang II-induced blood pressure increase was independent of Mfap4 genotype, ApoE−/−Mfap4−/− mice exhibited significantly lower AAA incidence and reduced maximal aortic diameter compared to ApoE−/− littermates. The ApoE−/−Mfap4−/− AAAs were further characterized by reduced macrophage infiltration, matrix metalloproteinase (MMP)-2 and MMP-9 activity, proliferative activity, collagen content, and elastic membrane disruption. MFAP4 deficiency also attenuated activation of integrin- and TGF-β-related signaling within the adventitial layer of AAA tissues. Finally, MFAP4 stimulation promoted human monocyte migration and significantly upregulated MMP-9 activity in macrophage-like THP-1 cells.Conclusion: This study demonstrates that MFAP4 induces macrophage-rich inflammation, MMP activity, and maladaptive remodeling of the ECM within the vessel wall, leading to an acceleration of AAA development and progression. Collectively, our findings suggest that MFAP4 is an essential aggravator of AAA pathology that acts through regulation of monocyte influx and MMP production.

Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix (ECM) protein primarily located in elastic arteries. It can bind elastin and collagen, and furthermore activate vascular cells through cellular integrin binding and modulate matrix metalloprotinase (MMP) activity. We hypothesized that lack of MFAP4 would decrease vascular inflammation and abdominal aortic aneurysm (AAA) formation. AAA was induced in 9-11 week old mice using two experimental mouse models: 1) Male Mfap4 -/- /ApoE -/- double knock-out (dKO) and ApoE -/- littermate control mice were feed western diet and subjected to continuously angiotensin II (AngII, 1000 ng/kg/min) infusion for 9-28 days via subcutaneous osmotic mini-pumps. Arterial blood pressure was measured in the femoral artery. 2) 1.5 U/mL elastase was infused into the infrarenal aorta in Mfap4 -/- and littermate Mfap4 +/+ mice for 5 minutes. Aortic blood flow was restored and the mice recovered for 9-16 days. Aortic diameter was measured in mice subjected to AngII or elastase infusion at day 28 and 16 respectively. MMP activity was detected by zymography. No difference in AAA formation was observed between genotypes after elastase perfusion. In response to AngII infusion dKO mice showed a significantly decrease in AAA diameter and incidence rate compared to ApoE -/- mice. AngII-induced increase in blood pressure was not dependent of MFAP4. However, there was decreased aortic arch atherosclerotic plaque formation, MMP2 and MMP9 activity in aortic tissue from dKO mice compared to ApoE -/- mice. Furthermore there was a non-significant tendency of decreased elastin degradation score in the AngII infused dKO mice, however this was not observed in the elastase perfused mice. Activity of MMP12 and extent of infiltrating leukocytes in aneurysmal tissue from both models will be further investigated. In conclusion we observed a decreased AAA formation and MMP activity in Mfap4 -/- /ApoE -/- mice which was not explained by variation in blood pressure or altered elastin degradation. The data suggest that MFAP4 induces MMP2-activity and thus the propensity for AAA formation.