The Role Of SR-A1/VEGF-B Axis In Obesity-Associated Hypertension And Underlying Mechanisms

Objectives:Cardiovascular disease is the leading cause of death in the world currently,and its morbidity and mortality are still increasing with years.As an important risk factor for cardiovascular disease,obesity can lead to a cascade of cardiovascular disorders.Studies indicate that 75%of patients with primary hypertension are associated with obesity.In recent years,adipose tissue has been a key target for treating obesity-related cardiovascular diseases.However,the mechanisms behind it are not clear.Perivascular adipose tissue（PVAT）surrounds most blood vessels in humans,apart from the vasculature in the brain.In obesity,PVAT becomes dysfunctional with adipose tissue expanding.Macrophages are the most abundant immune cells in the adipose tissue,and macrophage infiltration is positively correlated with the degree of obesity.Changes in macrophage phenotype also affect PVAT function,but the specific molecular mechanism still needs to be explored.Class A1 scavenger receptor（SR-A1）is one of the major pattern recognition receptors in modulating macrophage activity.We have previously reported that SR-A1 could protect against obesity-induced insulin resistance through inhibiting macrophage inflammation response in the adipose tissue.In addition,SR-A1 deficiency could aggravate the obesity-induced blood pressure（BP）elevation and increase VEGF-B expression in the obese PVAT.In the present study,we aimed to further investigate the role of SR-A1/VEGF-B axis in obesity-related hypertension.Methods:We used a high fat diet（HFD）-induced obese mice model to study the obesity-related BP elevation and vascular dysfunction.Firstly,immunofluorescence staining and flow cytometry were used to detect the expression and cell localization of SR-A1 in PVAT and aortae.Then we examined the expression of ICAM-1 in the aortae to confirm the protective effect of SR-A1 on endothelial function by immunofluorescence staining.In order to investigate the protective mechanism of SR-A1 against the obesity-related BP elevation and vascular dysfunction,we used HFD-induced obese mice and ob/ob mice to test the effect of SR-A1 deficiency on endothelial lipid accumulation by RT-q PCR and immunofluorescence staining.Furthermore,we observed the inhibitory effect of SR-A1 on macrophage-derived VEGF-B in the obese PVAT by western blot and immunofluorescence staining.Then we operated VEGF-B overexpression experiments to verify the role of SR-A1/VEGF-B pathway in the obesity-induced BP elevation and endothelial dysfunction.Lentiviruses expressing Vegf-b or control virus were injected into wild-type mice and SR-A1^-/-mice fed with HFD for 2 weeks.The BP of mice was monitored for 4 weeks by radiotelemetry technique after the lentivirus treatment.Then,we isolated aortae of mice injected with lentivirus to measure the endothelial-dependent relaxation response（EDR）.Fucoidan,a ligand of SR-A1,was used to verify the potential therapeutic effect of SR-A1/VEGF-B pathway.Wild-type mice and SR-A1^-/-mice fed with HFD for 8 weeks were injected intraperitoneally with fucoidan.The BP of mice was monitored 8 weeks after the injection,and the mice were sacrificed to detect EDR after 10 weeks of continuous BP monitoring.In addition,the expression of VEGF-B and inflammatory cytokines in PVAT and endothelial lipid accumulation were detected by RT-q PCR,western blot and immunofluorescence staining.Results:We found that whether in healthy mice or obese mice,SR-A1 was mainly expressed in macrophages of both the PVAT and aortae by immunofluorescence staining and flow cytometry.But in the obese PVAT,SR-A1 in F4/80⁺macrophages was reduced significantly.SR-A1 deficiency not only exacerbated the obesity-induced BP elevation and endothelial dysfunction in mice,but also significantly aggravated aortic endothelial lipid accumulation and increased macrophage-derived VEGF-B expression in PVAT.In vitro experiments also confirmed that VEGF-B could promote lipid accumulation in endothelial cells and aggravate palmitic acid（PA）-induced endothelial dysfunction.Overexpression of VEGF-B aggravated the obesity-induced BP elevation and endothelial dysfunction,but this effect was significantly reduced when SR-A1 was absent.Administration of fucoidan antagonized the obesity-induced BP elevation and endothelial dysfunction,and this effect relied on the expression of SR-A1.In addition,fucoidan administration significantly inhibited obesity-induced endothelial lipid accumulation and VEGF-B overexpression in PVAT.Conclusions:In obesity,SR-A1 inhibited macrophage-derived VEGF-B expression in PVAT,prevented endothelial lipid accumulation and obesity-induced BP elevation.The agonist of SR-A1 could antagonize the obesity-induced hypertension and endothelial dysfunction through inhibiting VEGF-B expression in PVAT.Therefore,we proposed that SR-A1/VEGF-B axis may be a potential target for the prevention and treatment of obesity-related hypertension.