Neutralizing endocan reduces blood pressure and improves endothelial function in angiotensin II-induced hypertensive mice.

Endocan (endothelial cell-specific molecule-1) has emerged as a potential biomarker of endothelial dysfunction in hypertension. This study investigates the role of endocan in blood pressure regulation and vascular dysfunction, aiming to clarify its contribution to the pathophysiology of hypertension. Eight-week-old male C57BL/6 mice were treated with saline, endocan (0.6 mg/kg), or angiotensin II (Ang II, 1000 ng/kg/min) for 4 weeks. Ang II-induced hypertensive mice were further treated with either control IgG or neutralizing endocan antibody (9 μg/mouse). Systolic blood pressure was measured by tail-cuff methods, and vascular function was assessed in mesenteric resistance arteries using a wire myograph. Serum endocan levels were quantified via enzyme-linked immunosorbent (ELISA) assay. Human umbilical vein endothelial cells (HUVECs) were treated with varying concentrations of Ang II, endocan, tumor necrosis factor-α (TNF-α), or endocan with or without TNF-α inhibitor, etanercept, followed by analysis of phosphorylated eNOS (Ser1177) via western blot and nitrite levels via Griess assay. Endocan administration significantly increased blood pressure and impaired endothelium-dependent relaxation. Administration of Ang II increased serum endocan levels, and treatment of neutralizing endocan antibody reduced blood pressure and improved endothelial function in hypertensive mice. Ang II also increased endocan expression in HUVECs in a dose-dependent manner. Both Ang II and endocan reduced eNOS phosphorylation and nitrite levels in HUVECs. TNF-α levels were elevated in endocan- and Ang II-treated mice, and administration of TNF-α reduced eNOS phosphorylation in HUVECs. Notably, TNF-α inhibition reversed endocan-induced reductions in eNOS phosphorylation and nitrite levels. Our findings reveal a novel pathogenic mechanism whereby endocan drives endothelial dysfunction and hypertension through TNF-α-mediated eNOS suppression, establishing endocan as a promising therapeutic target for cardiovascular disease.