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    • br Materials and methods br Results br

    2021-09-22


    Materials and methods
    Results
    Discussion mmLDL is an important risk factor for cardiovascular disease, but its mechanism is still unclear. Previously, we co-cultured mmLDL with the coronary artery and basilar artery and found that mmLDL could upregulate ETB receptor expression in both [16], [17]; however, there has been no report on the effect of mmLDL on ETB receptor expression in vascular smooth muscle in whole animals. In this study, tail vein injection of mmLDL was shown for the first time to significantly increase the expression of mesenteric artery smooth muscle ETB receptors in mice, as well as increase the ETB receptor-mediated vasoconstriction and the serum concentration and vascular wall expression of ICAM-1 and VCAM-1. U0126 significantly inhibited these effects of mmLDL, indicating that the ERK1/2 pathway is involved in the mmLDL-induced upregulation of ETB receptor, ICAM-1 and VCAM-1 expression. The abnormal expression of vascular smooth muscle contractile receptors is closely related to cardiovascular disease. Cerebral blood flow reduction and subsequent cerebral ischemia are correlated with the upregulation of vascular smooth muscle contractile receptors [20], [21], [22], [23], while focal cerebral ischemia can directly induce the expression of vascular smooth muscle ETB receptors and increase S6c-mediated vasoconstriction, thereby accelerating the pathological changes in blood vessels after cerebral ischemia [6], [24], [25]. The forearm blood flow of patients with atherosclerosis was reduced, and the expression of smooth muscle contractile ETB receptors was upregulated; however, the use of the ETB receptor antagonist BQ788 significantly increased the vasodilatation and recovery of forearm blood flow [26]. Secondhand smoking has been shown to cause a significant increase in the expression of ETB receptors in the basilar and coronary scopolamine hydrobromide sale in rats that was related to ERK1/2 activity [9], [27]. The present study showed that tail vein injection of mmLDL increased the expression of mouse mesenteric artery smooth muscle ETB receptors without affecting the simultaneous measurements of the blood pressure. Vascular inflammation is an important phenomenon in cardiovascular disease that exists throughout the cardiovascular disease process and can, therefore, provide predictive information for the diagnosis of the disease. Vascular inflammation is the result of the interaction of circulating monocytes with vascular endothelial cells. ICAM-1, VCAM-1 and other adhesion molecules, as the media for the interaction between circulating monocytes and vascular endothelial cells, play an important role in the vascular inflammatory response. In the early stages of atherosclerosis, adhesion molecules mediate the adherence of monocytes to endothelial cells and migrate across the endothelium to the vascular smooth muscle layer, thereby initiating downstream events. In the resting state, the expression of adhesion molecules in vascular endothelial cells is low; however, under the induction of stimulatory factors such as tumor necrosis factor-α (TNF-α) [28] and interleukin-1β (IL-1β) [29], [30], the expression levels of adhesion molecules, ICAM-1 and VCAM-1, are both upregulated. We previously found that intravenous tail injection of mmLDL promoted an increase in the serum concentrations of inflammatory cytokines such as TNF-α and IL-1β as well their expression in the vessel wall [15], and this study showed that intravenous tail injection of mmLDL promoted the expression of adhesion molecules such as ICAM-1 and VCAM-1. U0126 is a selective inhibitor of MEK1/2 that inhibits the activation of downstream kinases ERK1/2 by inhibiting MEK1/2 activity and is therefore commonly used in studies of MAPK signal transduction within the cell. In this study, tail vein injection of mmLDL significantly increased ERK1/2 activity, indicated by the increase in the ERK1/2 phosphorylation level (increased p-ERK1/2); in contrast, the ERK1/2 selective inhibitor U0126 significantly inhibited this effect, consistent with findings from our previous report [15]. One in vitro study has shown that mmLDL can activate monocytes and further induce their adhesion to endothelial cells [2]. In vitro experiments have shown that co-culture of a rat basilar artery with IL-1β and TNF-α significantly increases the contractile function of the basilar artery by mediated ETB receptors [31]. In this study, we found that tail vein injection of mmLDL upregulated mouse mesenteric artery ETB receptors, significantly increasing ICAM-1 and VCAM-1 serum concentrations and vascular wall expression, while the ERK1/2 selective inhibitor U0126 significantly inhibited these effects. Linear correlation analyses showed that serum ICAM-1 and VCAM-1 concentrations were positively correlated with the ETB receptor-mediated maximum contraction of blood vessels.