Hydroxytyrosol targets extracellular matrix remodeling by endothelial cells and inhibits both ex vivo and in vivo angiogenesis

Background: MicroRNA-133a (miR133a) is a small non-coding RNA, which represses the translation of multiple mRNAs. This laboratory has reported an inverse relationship between aortic diameter and miR133a abundance in aortic tissue from patients with thoracic aortic aneurysm (TAA); as diameter increased, the abundance of miR133a decreased. Given that wall tension at a given pressure increases with increasing vessel diameter (Law of LaPlace), this study tested the hypothesis that elevated aortic wall tension results in a loss of miR-133a. Methods/Results: TAA was induced in wild type mice using an established murine model (0.5M CaCl 2 application, 15 min). MiR133a abundance (QPCR) was reduced in TAA tissue (3-wk TAA, 42.1±8.6% p<0.05 vs mice without TAA (100%)). In two in vivo models of elevated wall tension ( simulated hypertension ): 1) ANGII (angiotensin II infusion; 1.44mg/kg/day), and 2) BPH2 (spontaneously hypertensive mice, The Jackson Laboratory, Stock #003005), miR133a levels were decreased compared to normotensive controls (ANGII: 53.0±4.3%; BPH2: 51.7±7.0%; p<0.05 vs normotensive control (100%)). Aortic rings from wild type mice were hung on parallel wires in an ex vivo tissue myograph at 0.7 g, then ANGII (100nM) was added to the tissue baths, which generated increased tension (1.21±0.15g) and resulted in reduced tissue miR133a abundance (46.0±12%; p<0.05 vs no AngII,). Furthermore, increased tension alone (1.5g, 3 hr) resulted in decreased tissue miR133a abundance (39.0±7.0%; p<0.05 vs 0.7 g tension). Isolated primary aortic cell lines (fibroblasts (FB) and smooth muscle cells (SMC)) were exposed to biaxial cyclic stretch for 3 hr. FB miR133a was reduced (62.8±8.3%; p<0.05 vs unstretched control (100%)), while SMC miR133a abundance remained unchanged. Conclusion: The significance of these unique findings is 2-fold: First, tension alone was sufficient to decrease miR133a abundance in aortic tissue. Second, increased tension reduced miR133a abundance in FB, a cell type that is responsible for extracellular matrix remodeling. These findings suggest changes in wall tension alone ( hypertension ) may be associated with pathological extracellular matrix remodeling, in part, through the loss of miR133a in fibroblasts.

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Precision-Cut Kidney Slices as a Tool to Understand the Dynamics of Extracellular Matrix Remodeling in Renal Fibrosis

Biomarker Insights ◽

10.4137/bmi.s38439 ◽

2016 ◽

Vol 11 ◽

pp. BMI.S38439 ◽

Cited By ~ 7

Author(s):

Federica Genovese ◽

Zsolt S. Kàrpàti ◽

Signe H. Nielsen ◽

Morten A. Karsdal

Keyword(s):

Extracellular Matrix ◽

Collagen Type ◽

Interstitial Fibrosis ◽

Ex Vivo ◽

Collagen Type I ◽

Extracellular Matrix Remodeling ◽

Type I ◽

Matrix Remodeling ◽

Renal Interstitial Fibrosis ◽

Ex Vivo Model

The aim of this study was to set up an ex vivo model for renal interstitial fibrosis in order to investigate the extracellular matrix (ECM) turnover profile in the fibrotic kidney. We induced kidney fibrosis in fourteen 12-week-old male Sprague Dawley rats by unilateral ureteral obstruction (UUO) surgery of the right ureter. The left kidney (contralateral) was used as internal control. Six rats were sham operated and used as the control group. Rats were terminated two weeks after the surgery; the kidneys were excised and precision-cut kidney slices (PCKSs) were cultured for five days in serum-free medium. Markers of collagen type I formation (P1NP), collagen type I and III degradation (C1M and C3M), and α-smooth muscle actin (αSMA) were measured in the PCKS supernatants by enzyme-linked immunosorbent assay. P1NP, C1M, C3M, and α-SMA were increased up to 2- to 13-fold in supernatants of tissue slices from the UUO-ligated kidneys compared with the contralateral kidneys ( P < 0.001) and with the kidneys of sham-operated animals ( P < 0.0001). The markers could also reflect the level of fibrosis in different animals. The UUO PCKS ex vivo model provides a valuable translational tool for investigating the extracellular matrix remodeling associated with renal interstitial fibrosis.

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Regulation of Extracellular Matrix Remodeling and MMP-2 activation in Cultured Rat Adrenal Medullary Endothelial Cells

Endothelium ◽

10.3109/10623320109051564 ◽

2001 ◽

Vol 8 (3) ◽

pp. 181-194 ◽

Cited By ~ 3

Author(s):

E. Papadimitriou ◽

C. R. Waters ◽

V. G. Manolopoulos ◽

B. R. Unsworth ◽

M. E. Maragoudakis ◽

...

Keyword(s):

Extracellular Matrix ◽

Endothelial Cells ◽

Extracellular Matrix Remodeling ◽

Matrix Remodeling

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Expression of gelatinase A, a mediator of extracellular matrix remodeling, by tracheal gland serous cells in culture and in vivo.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)47272-9 ◽

1994 ◽

Vol 269 (41) ◽

pp. 25454-25464

Author(s):

J M Tournier ◽

M Polette ◽

J Hinnrasky ◽

J Beck ◽

Z Werb ◽

...

Keyword(s):

Extracellular Matrix ◽

Extracellular Matrix Remodeling ◽

Matrix Remodeling ◽

Gelatinase A ◽

Cells In Culture

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Vitamin D deficiency promotes large rupture-prone abdominal aortic aneurysms and cholecalciferol supplementation limits progression of aneurysms in a mouse model

Clinical Science ◽

10.1042/cs20200980 ◽

2020 ◽

Vol 134 (18) ◽

pp. 2521-2534 ◽

Cited By ~ 1

Author(s):

Vianne Nsengiyumva ◽

Smriti M. Krishna ◽

Corey S. Moran ◽

Joseph V. Moxon ◽

Susan K. Morton ◽

...

Keyword(s):

Vitamin D ◽

Extracellular Matrix ◽

Mouse Model ◽

Vitamin D Deficiency ◽

Ex Vivo ◽

Aortic Aneurysms ◽

Matrix Metalloproteinase 2 ◽

Extracellular Matrix Remodeling ◽

Matrix Remodeling ◽

Abdominal Aortic

Abstract Vitamin D deficiency has been associated with human abdominal aortic aneurysm (AAA); however, its role in AAA pathogenesis is unclear. The aim of the present study was to investigate the effect of vitamin D deficiency on AAA development and examine if administering cholecalciferol (CCF) could limit growth of established AAA within the angiotensin-II (AngII) infused apolipoprotein E-deficient mouse model. Mice were rendered vitamin D deficiency through dietary restriction and during AngII infusion developed larger AAAs as assessed by ultrasound and ex vivo morphometry that ruptured more commonly (48% vs. 19%; P=0.028) than controls. Vitamin D deficiency was associated with increased aortic expression of osteopontin and matrix metalloproteinase-2 and -9 than controls. CCF administration to mice with established aortic aneurysms limited AAA growth as assessed by ultrasound (P<0.001) and ex vivo morphometry (P=0.036) and reduced rupture rate (8% vs. 46%; P=0.031). This effect was associated with up-regulation of circulating and aortic sclerostin. Incubation of human aortic smooth muscle cells with 1,25-dihyroxyvitamin D3 (the active metabolite of vitamin D) for 48 h induced up-regulation of sclerostin (P<0.001) and changed the expression of a range of other genes important in extracellular matrix remodeling. The present study suggests that vitamin D deficiency promotes development of large rupture-prone aortic aneurysms in an experimental model. CCF administration limited both growth and rupture of established aneurysms. These effects of vitamin D appeared to be mediated via changes in genes involved in extracellular matrix remodeling, particularly sclerostin.

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