ER stress dependent microparticles derived from smooth muscle cells promote endothelial dysfunction during thoracic aortic aneurysm and dissection

Abstract

The degeneration of vascular smooth muscle cell(s) (SMC) is one of the key features of thoracic aortic aneurysm and dissection (TAAD). We and others have shown that elevated endoplasmic reticulum (ER) stress causes SMC loss and TAAD formation, however, the mechanism of how SMC dysfunction contributes to intimal damage, leading to TAAD, remains to be explored. In the present study, in vitro assay demonstrated that elevated mechanical stretch (18% elongation, 3600 cycles/h) stimulated the ER stress response and microparticle(s) (MP) production from both SMC and endothelial cell(s) (EC) in a time-dependent manner. Treatment of EC with isolated MP led to anoikis, which was determined by measuring the fluorescence of the ethidium homodimer (EthD-1) and Calcein AM cultured in hydrogel-coated plates and control plates. MP stimulation of EC also up-regulated the mRNA levels of inflammatory molecules (i.e. Vascular cellular adhesion molecular-1 (VCAM-1)), intercellular adhesion molecular-1 (ICAM-1), interleukin-1β (IL-1β), and interleukin-6 (IL-6)). Use of an ER stress inhibitor or knockout of CHOP decreased mechanical stretch-induced MP production in SMC. In vivo, administration of an ER stress inhibitor or knockout of CHOP suppressed both apoptosis of EC and the infiltration of inflammatory cells. Moreover, TAAD formation was also suppressed by the administration of an ER stress inhibitor. In conclusion, our study demonstrates that elevated mechanical stretch induces MP formation in SMC leading to endothelial dysfunction, which is ER stress dependent. The inhibition of ER stress suppressed EC apoptosis, inflammation in the aorta, and TAAD development.

CD40L promotes development of acute aortic dissection via induction of inflammation and impairment of endothelial cell function

“…For example, CD40L is proved to increase neointimal formation after arterial injury and is proved to activate platelets and further trigger an inflammatory reaction of endothelial cells [ 21 – 23 ]. Moreover, endothelial dysfunction was previously elucidated to play a role in AAD development by endoplasmic reticulum (ER) stress dependent microparticles derived from smooth muscle cells [ 24 ]. However, to our knowledge, no one have ever investigated the effects of CD40L on the endothelial cells of aorta.…”

“…And not surprisingly, TNF-α and IL-2 plasma levels were found significantly higher [ 34 ]. With regard to IL-1β and ICAM-1, Jia LX et al confirmed larger expression of mRNA in aorta specimens of AAD patients and mouse [ 24 ]. In addition, ICAM-1 has been identified to be a risk factor for spontaneous cervical artery dissection [ 35 ].…”

Extracellular vesicles in cardiovascular homeostasis and disease

“…Endoplasmic reticulum stress leads to production of SMC-derived EVs, which promote endothelial cell dysfunction in a model of thoracic aortic aneurysm [10]. Classically, endothelial cell dysfunction leads to expression of adhesion proteins that aid in the translocation of leukocytes from the blood into vascular tissue, wherein these cells contribute to vascular wall remodeling.…”

Effect of “Nourishing Yin and Qi, Promoting Blood Circulation and Detoxification” on Endoplasmic Reticulum Stress CHOP Apoptotic Bypass in Diabetic Atherosclerosis

“…Moreover, endothelial cells, smooth muscle cells and mononuclear macrophages in the arterial wall can also oxidize LDL to form ox-LDL, which is highly affinity to macrophage scavenger receptor, with no negative feedback mechanism, resulting in the accumulation of cholesteryl esters in macrophages to form foam cells [13][14]. In addition, the accumulation of excessive metabolites such as cholesterol, free fatty acids, AGEs, homocysteine in smooth muscle cells and monocyte macrophages caused by diabetes mellitus can persistently over-activate the unfolded protein response, leading to the activation of IRE1, PERK and ATF6 signaling pathways [15]. On the one hand, when IRE1 is activated, it binds with TRAF2 to form IRE1α-TRAF2 complex, which can recruit IkB kinase, phosphorylate and degrade IkB, release NF-kB into nucleus and activate the transcription of pro-inflammatory genes.…”