Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure

Abstract

Endothelial dysfunction is a critical factor in many cardiovascular diseases, including hypertension. Although lipid signaling has been implicated in endothelial dysfunction and cardiovascular disease, specific molecular mechanisms are poorly understood. Here we report that Nogo-B, a membrane protein of the endoplasmic reticulum, regulates endothelial sphingolipid biosynthesis with direct effects on vascular function and blood pressure. Nogo-B inhibits serine palmitoyltransferase, the rate-limiting enzyme of the de novo sphingolipid biosynthetic pathway, thereby controlling production of endothelial sphingosine 1-phosphate and autocrine, G protein–coupled receptor–dependent signaling by this metabolite. Mice lacking Nogo-B either systemically or specifically in endothelial cells are hypotensive, resistant to angiotensin II–induced hypertension and have preserved endothelial function and nitric oxide release. In mice that lack Nogo-B, pharmacological inhibition of serine palmitoyltransferase with myriocin reinstates endothelial dysfunction and angiotensin II–induced hypertension. Our study identifies Nogo-B as a key inhibitor of local sphingolipid synthesis and shows that autocrine sphingolipid signaling within the endothelium is critical for vascular function and blood pressure homeostasis.

S1P Signaling and De Novo Biosynthesis in Blood Pressure Homeostasis

“…Once produced, S1P is transported out of ECs through the spinster-2 transporter (Fukuhara et al, 2012), where it activates S1PR1 on the cell surface to induce barrier protective functions and control vascular tone in an autocrine manner (Cantalupo et al, 2015); additionally, it binds to protein carriers such as albumin (35%) and high-density lipoprotein (HDL) (60%), and to a lesser extent to lowdensity and very low-density lipoproteins (Murata et al, 2000). Christoffersen et al (2011) showed that in mice lacking apolipoprotein M (ApoM), HDL has no S1P content, indicating that S1P binds to HDL through ApoM.…”

“…The endothelium is not only a target but also an important source of plasma S1P. Recent studies reveal a novel role of endothelial-derived S1P and autocrine S1P-S1PR1 signaling in flow-mediated vasodilation (Jung et al, 2012;Cantalupo et al, 2015). Jung et al (2012) reported that flow-induced EC alignment and eNOS activation were suppressed in the absence of S1PR1, both in vitro and in vivo.…”

“…Jung et al (2012) reported that flow-induced EC alignment and eNOS activation were suppressed in the absence of S1PR1, both in vitro and in vivo. By using the pressure myograph system, Cantalupo et al (2015) demonstrated that the endothelial S1P-S1PR1-eNOS autocrine loop is physiologically active in regulating vascular tone in response to flow. In control mice, W146 markedly reduced flow-induced vasodilation of mesenteric arteries in a concentration-dependent manner [ Fig.…”

“…In control mice, W146 markedly reduced flow-induced vasodilation of mesenteric arteries in a concentration-dependent manner [ Fig. 2, adapted from Cantalupo et al (2015)] as well as eNOS activation, with a subsequent increase in myogenic tone (Cantalupo et al, 2015).…”

WITHDRAWN: Endothelial Nogo-B suppresses cancer cell proliferation via a paracrine TGF-β/Smad signaling

“…Nogo-B knockout (Nogo-B-/-) mice exhibit impaired arteriogenesis, indicating an essential role for Nogo-B in physiological angiogenesis [9]. Nogo-B knockout animals exhibit excessive repair of the intimal and medial layers of the balloon traction-injured femoral artery, which was remedied upon the restoration of Nogo-B expression, suggesting a critical role for Nogo-B in vascular remodeling [11,12]. Nevertheless, role of vascular endothelial Nogo-B in cancer development largely remains unknown.…”