MiR-126-5p promotes contractile switching of aortic smooth muscle cells by targeting VEPH1 and alleviates Ang II-induced abdominal aortic aneurysm in mice

Objective: Excessive prostaglandin E 2 production is a hallmark of abdominal aortic aneurysm (AAA). Enhanced expression of prostaglandin E 2 receptor EP4 (prostaglandin E receptor 4) in vascular smooth muscle cells (VSMCs) has been demonstrated in human AAAs. Although moderate expression of EP4 contributes to vascular homeostasis, the roles of excessive EP4 in vascular pathology remain uncertain. We aimed to investigate whether EP4 overexpression in VSMCs exacerbates AAAs. Approach and Results: We constructed mice with EP4 overexpressed selectively in VSMCs under an SM22α promoter (EP4-Tg). Most EP4-Tg mice died within 2 weeks of Ang II (angiotensin II) infusion due to AAA, while nontransgenic mice given Ang II displayed no overt phenotype. EP4-Tg developed much larger AAAs than nontransgenic mice after periaortic CaCl 2 application. In contrast, EP4 fl/+ ;SM22-Cre;ApoE −/ − and EP4 fl/+ ;SM22-Cre mice, which are EP4 heterozygous knockout in VSMCs, rarely exhibited AAA after Ang II or CaCl 2 treatment, respectively. In Ang II–infused EP4-Tg aorta, Ly6C hi inflammatory monocyte/macrophage infiltration and MMP-9 (matrix metalloprotease-9) activation were enhanced. An unbiased analysis revealed that EP4 stimulation positively regulated the genes binding cytokine receptors in VSMCs, in which IL (interleukin)-6 was the most strongly upregulated. In VSMCs of EP4-Tg and human AAAs, EP4 stimulation caused marked IL-6 production via TAK1 (transforming growth factor-β–activated kinase 1), NF-κB (nuclear factor-kappa B), JNK (c-Jun N-terminal kinase), and p38. Inhibition of IL-6 prevented Ang II–induced AAA formation in EP4-Tg. In addition, EP4 stimulation decreased elastin/collagen cross-linking protein LOX (lysyl oxidase) in both human and mouse VSMCs. Conclusions: Dysregulated EP4 overexpression in VSMCs promotes inflammatory monocyte/macrophage infiltration and attenuates elastin/collagen fiber formation, leading to AAA exacerbation.

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Histochemical and immunohistochemical analysis of ruptured atherosclerotic abdominal aortic aneurysm wall

Vojnosanitetski pregled ◽

10.2298/vsp1012959t ◽

2010 ◽

Vol 67 (12) ◽

pp. 959-964 ◽

Cited By ~ 6

Author(s):

Irena Tanaskovic ◽

Aleksandra Mladenovic-Mihailovic ◽

Slavica Usaj-Knezevic ◽

Vesna Stankovic ◽

Aleksandar Aleksic ◽

...

Keyword(s):

Smooth Muscle ◽

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Smooth Muscle Cells ◽

Periodic Acid ◽

Muscle Cells ◽

Foam Cells ◽

Abdominal Aortic ◽

S 100 ◽

The Media

Background/Aim. The main complication of the atherosclerotic abdominal aortic aneurism (AAA) is her rupture that begins with lesion in intima and rupture. The purpose of this work was to determine immunocytochemical and morphofunctional characteristics of the cells in aortic wall in ruptured atherosclerotic abdominal aortic aneurysm. Method. During the course of this study, 20 samples of atherosclerotic AAA were analyzed, all of them obtained during authopsy. The samples were fixed in 4% formalin and embedded in paraffin. Sections of 5 ?m thickness were stained histochemically (of Heidenhain azan stain and Periodic acid Schiff - PAS stain) and immunocytochemically using a DAKO LSAB+/HRP technique to identify ?-smooth muscle actin (?-SMA), vimentin, myosin heavy chains (MHC), desmin, S-100 protein, CD45 and CD68 (DAKO specification). Results. The results of our study showed that ruptured atherosclerotic AAA is characterized by a complete absence of endothelial cells, the disruption of basal membrane and internal elastic lamina, as well as a presence of the remains of hypocellular complicated atherosclerotic lesion in intima. On the plaque margins, as well as in the media, smooth muscle cells (SMCs) are present, which express a ?-SMA and vimentin (but without MHC or desmin expression), as well as leukocyte infiltration, and a large number of foam cells. Some of the foam cells show a CD68-immunoreactivity, while the others show vimentin- and S-100 protein-immunoreactivity. Media is thinned out with a disorganized elastic lamellas, while adventitia is characterized by inflammatory inflitrate (infection). Conclusion. Rupture of aneurysm occurs from the primary intimal disruption, which spreads into thinned out media and adventitia. Rupture is caused by unstable atherom, hypocellularity, loss of contractile characteristics of smooth muscle cells in intima and media, neovascularization of the media, as well as by the activity of the macrophages in the lesion.

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Peri-Adventitial Delivery of Smooth Muscle Cells in Porous Collagen Scaffolds for Treatment of Experimental Abdominal Aortic Aneurysm

Biomaterials Science ◽

10.1039/d1bm00685a ◽

2021 ◽

Author(s):

Joscha Mulorz ◽

Mahdis Shayan ◽

Caroline Hu ◽

Cynthia Alcazar ◽

Alex H.P Chan ◽

...

Keyword(s):

Smooth Muscle ◽

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Vessel Wall ◽

Muscle Cells ◽

Collagen Scaffolds ◽

Abdominal Aortic ◽

Direct Delivery

Abdominal aortic aneurysm (AAA) is associated with the loss of vascular smooth muscle cells (SMCs) within the vessel wall. Direct delivery of therapeutic cells is challenging due to impaired mechanical...

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ANG II increases TIMP-1 expression in rat aortic smooth muscle cells in vivo

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00986.2001 ◽

2003 ◽

Vol 284 (2) ◽

pp. H635-H643 ◽

Cited By ~ 41

Author(s):

Giovanna Castoldi ◽

Cira R. T. di Gioia ◽

Federico Pieruzzi ◽

Cristina D'Orlando ◽

Willy M. M. van de Greef ◽

...

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Muscle Cells ◽

Vascular Wall ◽

Dependent Manner ◽

Ang Ii ◽

Maximal Increase ◽

Aortic Smooth Muscle Cells ◽

Aortic Smooth Muscle

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in tissue remodeling processes. TIMP-1 is the main native inhibitor of MMPs and it contributes to the development of tissue fibrosis. It is known that ANG II plays a fundamental role in vascular remodeling. In this study, we investigated whether ANG II modulates TIMP-1 expression in rat aortic smooth muscle cells. In vitro, ANG II induces TIMP-1 mRNA expression in a dose-dependent manner. The maximal increase in TIMP-1 expression was present after 3 h of ANG II stimulation. The ANG II increase in TIMP-1 expression was mediated by the ANG type 1 receptors because it was blocked by losartan. The increase in TIMP-1 expression was present after the first ANG II treatment, whereas repeated treatments (3 and 5 times) did not modify TIMP-1 expression. In vivo, exogenous ANG II was administered to Sprague-Dawley rats (200 ng · kg−1· min−1sc) for 6 and 25 days. Control rats received physiological saline. After treatment, systolic blood pressure was significantly higher ( P < 0.01), whereas plasma renin activity was suppressed ( P < 0.01), in ANG II-treated rats. ANG II increased TIMP-1 expression in the aorta of ANG II-treated rats both at the mRNA ( P < 0.05) and protein levels as evaluated by Western blotting ( P < 0.05) and/or immunohistochemistry. Neither histological modifications at the vascular wall nor differences in collagen content in the tunica media were present in both the ANG II- and saline-treated groups. Our data demonstrate that ANG II increases TIMP-1 expression in rat aortic smooth muscle cells. In vivo, both short- and long-term chronic ANG II treatments increase TIMP-1 expression in the rat aorta. TIMP-1 induction by ANG II in aortic smooth muscle cells occurs in the absence of histological changes at the vascular wall.

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Macrophage-derived netrin-1 promotes abdominal aortic aneurysm formation by activating MMP3 in vascular smooth muscle cells

Nature Communications ◽

10.1038/s41467-018-07495-1 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 17

Author(s):

Tarik Hadi ◽

Ludovic Boytard ◽

Michele Silvestro ◽

Dornazsadat Alebrahim ◽

Samson Jacob ◽

...

Keyword(s):

Smooth Muscle ◽

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Muscle Cells ◽

Aneurysm Formation ◽

Abdominal Aortic

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Mechanism of angiotensin II-induced arachidonic acid metabolite release in aortic smooth muscle cells: involvement of phospholipase D

Acta Endocrinologica ◽

10.1530/eje.0.1360207 ◽

1997 ◽

Vol 136 (2) ◽

pp. 207-212 ◽

Cited By ~ 6

Author(s):

Junji Shinoda ◽

Osamu Kozawa ◽

Atsushi Suzuki ◽

Yasuko Watanabe-Tomita ◽

Yutaka Oiso ◽

...

Keyword(s):

Arachidonic Acid ◽

Smooth Muscle ◽

Angiotensin Ii ◽

Smooth Muscle Cells ◽

Phospholipase D ◽

Muscle Cells ◽

Dependent Manner ◽

Ang Ii ◽

Aortic Smooth Muscle Cells ◽

Aortic Smooth Muscle

Abstract In a previous study, we have shown that angiotensin II (Ang II) activates phosphatidylcholinehydrolyzing phospholipase D due to Ang II-induced Ca2+ influx from extracellular space in subcultured rat aortic smooth muscle cells. In the present study, we have investigated the role of phospholipase D in Ang II-induced arachidonic acid (AA) metabolite release and prostacyclin synthesis in subcultured rat aortic smooth muscle cells. Ang II significantly stimulated AA metabolite release in a concentration-dependent manner in the range between 1 nmol/l and 0·1 μmol/l. d,l-Propranolol hydrochloride (propranolol), an inhibitor of phosphatidic acid phosphohydrolase, significantly inhibited the Ang II-induced release of AA metabolites. The Ang II-induced AA metabolite release was reduced by chelating extracellular Ca2+ with EGTA. Genistein, an inhibitor of protein tyrosine kinases, significantly suppressed the Ang II-induced AA metabolite release. 1,6-Bis-(cyclohexyloximinocarbonylamino)-hexane (RHC-80267), a potent and selective inhibitor of diacylglycerol lipase, significantly inhibited the Ang II-induced AA metabolite release. Both propranolol and RHC-80267 inhibited the Ang II-induced synthesis of 6-keto-prostaglandin F1α, a stable metabolite of prostacyclin. The synthesis was suppressed by genistein. These results strongly suggest that the AA metabolite release induced by Ang II is mediated, at least in part, through phosphatidylcholine hydrolysis by phospholipase D activation in aortic smooth muscle cells. European Journal of Endocrinology 136 207–212

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