Abstract
Adhesion of monocytes to the vascular endothelium frequently leads to an inflammatory response, which contributes to hypertension and vascular remodeling. Vascular cellular adhesion molecule-1 (VCAM-1) plays an important role in leukocyte adhesion and migration during inflammatory diseases. However, its role in angiotensin (Ang) II -induced hypertension and vascular dysfunction remains largely unknown. Wild-type (WT) mice were administered a VCAM-1 neutralizing antibody (0.1 or 0.2 mg/mouse/day) or IgG control and then infused with Ang II (490 ng kg−1 min−1) or saline continuously for 14 days. Systolic blood pressure (SBP) was measured with a tail-cuff system, pathological changes in the aorta were assessed by histological staining, and vascular relaxation was analyzed an aortic ring assay. Our results indicated that compared with saline infusion, Ang II infusion significantly upregulated VCAM-1 expression in the mouse aorta and serum. Moreover, Ang II infusion markedly increased arterial hypertension, wall thickness, fibrosis, infiltration of Mac-2+ macrophages, reactive oxygen species (ROS) production and vascular relaxation dysfunction. Conversely, blockade of VCAM-1 with a neutralizing antibody substantially alleviated these effects. In vitro experiments further confirmed that the VCAM-1 neutralizing antibody inhibited Ang II-induced macrophage adhesion and migration and DNA damage and oxidative stress in endothelial cells (ECs). In conclusion, these results indicate that blockade of VCAM-1 exerts a protective effect against Ang II-induced arterial hypertension and dysfunction by regulating monocytes adhesion and infiltration into the endothelium and represents a novel therapeutic approach for hypertension.
Highlights
Hypertension is the primary risk factor for various cardiovascular diseases (CVDs), which are associated with high morbidity and mortality worldwide (Dorans et al, 2018)
To determine the involvement of Vascular cellular adhesion molecule-1 (VCAM-1) in Ang II-induced hypertension and vascular dysfunction, we first evaluated VCAM1 levels in the aorta after Ang II infusion for 14 days qPCR and immunoblot analysis revealed that VCAM-1 mRNA and protein levels were significantly higher in Ang II-infused aortas than in saline control-treated aortas (Figure 1A)
Our data showed that the Ang II-induced increases in serum VCAM-1 levels and Systolic blood pressure (SBP) were dose-dependently reduced in mice administered the VCAM-1 neutralizing antibody (Figures 2A,B), indicating that the VCAM1 neutralizing antibody effectively blocked VCAM-1 and inhibited hypertension in mice
Summary
Hypertension is the primary risk factor for various cardiovascular diseases (CVDs), which are associated with high morbidity and mortality worldwide (Dorans et al, 2018). The RAS has emerged as one of the most relevant factors in the occurrence and development of CVDs. Angiotensin (Ang) II, as a main peptide of the RAS, can stimulate vascular endothelial cells (ECs) to express cytokines, chemokines, growth factors and adhesion molecules, which are vital for regulating vascular pathophysiological processes, Blocking VCAM-1 Prevents Hypertension such as alterations in arterial tone, inflammatory responses, fibrosis, and extracellular matrix remodeling, through angiotensin type 1 receptor (AT1R) (Ruiz-Ortega et al, 2001). Experimental findings indicate that Ang II can promote monocyte but not neutrophil infiltration and maturation into proinflammatory macrophages and induce vascular dysfunction and arterial hypertension (Wenzel et al, 2011). Our recent study demonstrated that the adhesion molecule intercellular adhesion molecule-1 (ICAM-1) plays an important role in Ang II-induced hypertension and vascular dysfunction by promoting LFA-1+ monocyte adhesion to the endothelium (Lang et al, 2020), indicating that adhesion molecules are involved in hypertension and vascular dysfunction
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