Key result
ER stress inhibitors attenuate ET-1-induced inflammatory and contractile signaling in hypertensive vascular smooth muscle cells.
Why the study?
Endoplasmic reticulum stress (ERS) is implicated in hypertensive vascular injury, and endothelin-1 (ET-1) induces ERS in other diseases. However, the role of ET-1 in ERS in vascular smooth muscle cells (VSMCs) in hypertension remained unclear.
Does endothelin-1 signal through endoplasmic reticulum stress to induce vascular smooth muscle cell dysfunction in rat models of hypertension?
Does endothelin-1 signal through endoplasmic reticulum stress to induce vascular smooth muscle cell dysfunction in rat models of hypertension?
Endothelin-1 signals through endoplasmic reticulum stress (ERS) in vascular smooth muscle cells, and in hypertensive rat models, ET-1-induced pro-contractile, growth, and pro-inflammatory responses are amplified through ERS-dependent processes that can be attenuated by ERS inhibitors.
Background Hypertension is a multifactorial disease characterised by vascular dysfunction and remodelling. Vascular smooth muscle cells (VSMCs) are key players in vascular changes associated with hypertension. Vasoactive peptides play a vital role in vascular dysfunction in hypertension, including endothelin-1 (ET-1). ET-1 mediates effects through many pathways, including oxidative stress. Recent evidence in chronic kidney disease and preeclampsia suggest that ET-1 induces endoplasmic reticulum (ER) stress (ERS). ERS occurs when there is accumulation of misfolded proteins in the ER. This initiates an Unfolded Protein Response (UPR), activating protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α) and activating transcription factor 6 (ATF6). Chronic ERS triggers the UPR, causing inflammation, autophagy or apoptosis. ERS has been implicated in vascular injury in hypertension. We previously showed that markers of ERS (XBP1, ATF4) are increased in VSMCs from rat models of hypertension and that ET-1-induced expression of ATF4 is increased in hypertension. The role of ET-1 in ERS in VSMCs in hypertension is unclear. Aim Our study investigated the relationship between ERS and ET-1 signalling in VSMCs and questioned whether ET-1-induced signalling involves ERS in hypertension. Methods VSMCs from mesenteric arteries of normotensive Wistar- Kyoto Rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) were used. Expression of ERS markers (ATF4, XBP1), activation of pro-contractile signalling molecules (MLC20) and growth (ERK1/2) were assessed by immunoblotting after ET-1(100nM) stimulation in the presence or absence of ERS inhibitors (4-PBA, chemical chaperone,1mM; STF083010, IRE1 inhibitor, 60uM; GSK2606414, PERK inhibitor, 5uM). In some studies we also investigated effects of Ang II and aldosterone on ERS markers, including pIRE1 and peIF2a. Results In VSMCs stimulated with ET-1, phosphorylation of ERK1/2 was increased in WKY and SHRSP VSMCs. These effects were inhibited by ERS inhibitors. ET-1 had no effect on MLC in WKY VSMCs. In SHRSP VSMCs, ET-1 increased MLC phosphorylation, effects that were reduced by ERS inhibitors. Expression of the pro-inflammatory mediator NFkB was increased by ET-1 only in SHRSP. This was attenuated by ERS inhibitors. Unlike ET-1, Ang II and aldosterone had no effect on pIRE1 and peIF2a (markers of ERS). Conclusion These results indicate that ET-1 signals through ERS in VSMCs and that in hypertension, ET-1 responses are amplified through ERS-dependent processes. These effects are not generalised phenomena because other vasoactive agents (Ang II and aldosterone) did not influence ERS in our models. Our findings suggest that ERS is an important player in ET-1-induced VSMC dysfunction in hypertension, supporting our earlier studies.
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Lam et al. (2026) studied Hypertension. Endothelin-1 (ET-1) stimulation with or without endoplasmic reticulum stress (ERS) inhibitors (4-PBA, STF083010, GSK2606414) vs. Absence of ERS inhibitors / normotensive WKY VSMCs / Angiotensin II and aldosterone stimulation was evaluated on Expression of ERS markers (ATF4, XBP1), phosphorylation of MLC20 and ERK1/2, and NFkB expression. ET-1 (100 nM) increased ERK1/2, MLC20, and NFkB signalling in hypertensive rat VSMCs, effects that were attenuated by ER stress inhibitors (1 mM 4-PBA, 60 uM STF083010, 5 uM GSK2606414).
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