Targeting the ASMase/S1P pathway protects from sortilin-evoked vascular damage in hypertension

Abstract

Sortilin has been positively correlated with vascular disorders in humans. No study has yet evaluated the possible direct effect of sortilin on vascular function. We used pharmacological and genetic approaches coupled with study of murine and human samples to unravel the mechanisms recruited by sortilin in the vascular system. Sortilin induced endothelial dysfunction of mesenteric arteries through NADPH oxidase 2 (NOX2) isoform activation, dysfunction that was prevented by knockdown of acid sphingomyelinase ( ASMase ) or sphingosine kinase 1. In vivo, recombinant sortilin administration induced arterial hypertension in WT mice. In contrast, genetic deletion of sphingosine-1-phosphate receptor 3 (S1P3) and gp91phox/NOX2 resulted in preservation of endothelial function and blood pressure homeostasis after 14 days of systemic sortilin administration. Translating these research findings into the clinical setting, we detected elevated sortilin levels in hypertensive patients with endothelial dysfunction. Furthermore, in a population-based cohort of 270 subjects, we showed increased plasma ASMase activity and increased plasma levels of sortilin, S1P, and soluble NOX2-derived peptide (sNOX2-dp) in hypertensive subjects, and the increase was more pronounced in hypertensive subjects with uncontrolled blood pressure. Our studies reveal what we believe is a previously unrecognized role of sortilin in the impairment of vascular function and in blood pressure homeostasis and suggest the potential of sortilin and its mediators as biomarkers for the prediction of vascular dysfunction and high blood pressure.

Targeting SIRT1 Rescues Age- and Obesity-Induced Microvascular Dysfunction in Ex Vivo Human Vessels

“…Detailed Methods Figures S1 through S5 Table S1 References [81][82][83][84][85][86][87][88][89][90][91][92][93][94]…”

Deciphering Mechanisms of Action of Sortilin/Neurotensin Receptor-3 in the Proliferation Regulation of Colorectal and Other Cancers

“…Recently, it was identified that Sortilin/NTSR3 acts as a receptor for the brain lipids carrier Apolipoprotein E (apoE), which confers the most important genetic risk factor for Alzheimer’s disease (AD), demonstrating the involvement of Sortilin/NTSR3 in the neuroprotective action of apoE in AD pathology [ 31 ]. Finally, the role of Sortilin/NTSR3 as a biomarker of risk in cardiovascular disorders in humans has been largely confirmed [ 32 , 33 ].…”

Advances in pathogenesis and treatment of essential hypertension

“…Sortilin, a member of the vacuolar protein sorting 10 (VPS10P) family of receptors, has been positively correlated with vascular and metabolic disorders (110). A recent study demonstrated that sortilin induced endothelial dysfunction of mesenteric arteries through NADPH oxidase 2 (NOX2) isoform activation, and the dysfunction could be prevented by knockdown of acid sphingomyelinase (ASMase) or sphingosine kinase 1 (111). Furthermore, plasma ASMase activity and plasma levels of sortilin increased in hypertensive subjects, especially in those with uncontrolled blood pressure (111).…”