Senescence Increases Choroidal Endothelial Stiffness and Susceptibility to Complement Injury: Implications for Choriocapillaris Loss in AMD

Cardiac diastolic dysfunction (DD) and diastolic heart failure is increasing in concert with obesity and aging population in the United States. In obese and diabetic women, DD is more common than in their male counterparts. This disproportionate increase in DD in obese females may partly explain their loss of sex-related cardiovascular (CV) disease protection. Recent studies have suggested a role for endothelial sodium channel (ENaC) activation in promotion of endothelial stiffness and suppression of flow- (nitric oxide) mediated vasodilation. Moreover, increased mineralocorticoid receptor (MR) activation mediated endothelial stiffness is promoted, in part, by ENaC activation. In this regard, we have recently reported increased plasma aldosterone levels, aortic and cardiac stiffness, and cardiac and vascular MR expression in female mice fed a high fat and high fructose diet (western diet [WD]). This increase in CV stiffness was prevented by very low dose MR antagonism. Accordingly, we hypothesized that inhibition of MR-mediated ENaC activation by using a very low dose of the ENaC inhibitor, amiloride would prevent cardiac stiffening (DD) in WD-fed female mice. Four week old C57BL6/J mice were fed a WD containing high fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) with or without a very low dose of amiloride (1mg/kg/day) for 16 weeks. Amiloride significantly attenuated WD-induced impairment of cardiac relaxation in vivo as measured by high resolution magnetic resonance imaging (MRI) as well as cardiac interstitial fibrosis as measured by immunohistochemistry by picrosirius red staining. Moreover, amiloride prevented the development of DD in obese female mice without having effects on blood pressure. These observations support a role for ENaC activation in diet-induced cardiac stiffening (DD) in obese females.

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981 DIET-INDUCED ENDOTHELIAL STIFFNESS, CELLULAR HYPOXIA, AND ABNORMAL ANGIOGENIC SIGNALING IN PREECLAMPSIA

Journal of Hypertension ◽

10.1097/01.hjh.0000420927.64030.ee ◽

2012 ◽

Vol 30 ◽

pp. e283-e284

Author(s):

Nancy Hart

Keyword(s):

Cellular Hypoxia ◽

Endothelial Stiffness

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Identification of oxLDL Components Affecting Endothelial Stiffness

Biophysical Journal ◽

10.1016/j.bpj.2010.12.1091 ◽

2011 ◽

Vol 100 (3) ◽

pp. 160a

Author(s):

Tzu Pin Shentu ◽

Dev K. Singh ◽

Papasani Subbaiah ◽

Michael Cho ◽

Irena Levitan

Keyword(s):

Endothelial Stiffness

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OxLDL increases endothelial stiffness, force generation, and network formation

The Journal of Lipid Research ◽

10.1194/jlr.m500439-jlr200 ◽

2006 ◽

Vol 47 (4) ◽

pp. 715-723 ◽

Cited By ~ 65

Author(s):

Fitzroy J. Byfield ◽

Saloni Tikku ◽

George H. Rothblat ◽

Keith J. Gooch ◽

Irena Levitan

Keyword(s):

Network Formation ◽

Force Generation ◽

Endothelial Stiffness

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oxLDL-induced decrease in lipid order of membrane domains is inversely correlated with endothelial stiffness and network formation

AJP Cell Physiology ◽

10.1152/ajpcell.00383.2009 ◽

2010 ◽

Vol 299 (2) ◽

pp. C218-C229 ◽

Cited By ~ 35

Author(s):

Tzu Pin Shentu ◽

Igor Titushkin ◽

Dev K. Singh ◽

Keith J. Gooch ◽

Papasani V. Subbaiah ◽

...

Keyword(s):

Network Formation ◽

Cell Stiffness ◽

Membrane Domains ◽

Collagen Gels ◽

Lipid Packing ◽

Angiogenic Potential ◽

Cell Contractility ◽

Lipid Order ◽

The Impact ◽

Endothelial Stiffness

Oxidized low-density lipoprotein (oxLDL) is a major factor in development of atherosclerosis. Our earlier studies have shown that exposure of endothelial cells (EC) to oxLDL increases EC stiffness, facilitates the ability of the cells to generate force, and facilitates EC network formation in three-dimensional collagen gels. In this study, we show that oxLDL induces a decrease in lipid order of membrane domains and that this effect is inversely correlated with endothelial stiffness, contractility, and network formation. Local lipid packing of cell membrane domains was assessed by Laurdan two-photon imaging, endothelial stiffness was assessed by measuring cellular elastic modulus using atomic force microscopy, cell contractility was estimated by measuring the ability of the cells to contract collagen gels, and EC angiogenic potential was estimated by visualizing endothelial networks within the same gels. The impact of oxLDL on endothelial biomechanics and network formation is fully reversed by supplying the cells with a surplus of cholesterol. Furthermore, exposing the cells to 7-keto-cholesterol, a major oxysterol component of oxLDL, or to another cholesterol analog, androstenol, also results in disruption of lipid order of membrane domains and an increase in cell stiffness. On the basis of these observations, we suggest that disruption of lipid packing of cholesterol-rich membrane domains plays a key role in oxLDL-induced changes in endothelial biomechanics.

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Abstract P293: Endothelial Sodium Channel Activation Promotes Vascular Stiffness in Obese Female Mice

Hypertension ◽

10.1161/hyp.68.suppl_1.p293 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Annayya Aroor ◽

Francisco I Ramirez-Perez ◽

Guanghong Jia ◽

Javad Habibi ◽

Vincent G DeMarco ◽

...

Keyword(s):

Sodium Channel ◽

Aortic Stiffness ◽

Low Dose ◽

Vascular Stiffness ◽

Obese Women ◽

High Fat ◽

Arterial Stiffening ◽

Female Mice ◽

High Fructose ◽

Endothelial Stiffness

Obesity-associated arterial stiffening is an independent predictor of cardiovascular disease (CVD) events. Although premenopausal non-obese women are protected against CVD, aortic stiffening in obese women is more common than in men. This disproportionate increase in vascular stiffness in obese females may partly explain their loss of sex-related CVD protection. Recent studies have suggested a role for endothelial sodium channel (ENaC) activation in promotion of endothelial stiffness and suppression of flow-(nitric oxide) mediated vasodilation. Increased mineralocorticoid receptor (MR) activation mediated endothelial stiffness is promoted, in part, by ENaC activation. In this regard, we have recently reported increased aortic stiffness, MR and ENaC expression and endothelial dysfunction in female mice fed a high fat and high fructose diet (western diet [WD]). This increase in aortic stiffness was prevented by very low dose MR antagonism. Accordingly, we hypothesized that inhibition of MR-mediated ENaC activation by using a very low dose of the ENaC inhibitor, amiloride, would prevent arterial stiffening and vascular dysfunction in WD-fed female mice. Four week old C57BL6/J mice were fed a WD containing high fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) with or without a very low dose of amiloride (1mg/kg/day) for 16 weeks. Amiloride significantly attenuated WD-induced increases in aortic stiffness in vivo as measured by pulse wave velocity as well as in vitro endothelial stiffness as measured by atomic force microscopy. Moreover, incubation of aortic explants with very low dose of amiloride (1 μM) inhibited WD-induced aortic stiffness in aorta explants from WD-fed female mice. Amiloride also prevented WD-induced impairment in acetylcholine-induced aortic vasodilatation and flow-mediated dilation in mesenteric arteries. Taken together, these observations support a role for ENaC activation in diet-induced vascular stiffening in obese females.

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Abstract P232: Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, Linagliptin, Prevents Aortic Stiffening and Vascular and Cardiac Diastolic Dysfunction Caused by Western Diet Feeding in Female Mice

Hypertension ◽

10.1161/hyp.66.suppl_1.p232 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Vincent G DeMarco ◽

Annayya Aroor ◽

Guanghong Jia ◽

Javad Habibi ◽

Mona Garro ◽

...

Keyword(s):

Diastolic Dysfunction ◽

Aortic Stiffness ◽

Vascular Reactivity ◽

Control Diet ◽

Western Diet ◽

Obese Women ◽

Dipeptidyl Peptidase 4 ◽

Force Microscopy ◽

Aortic Stiffening ◽

Endothelial Stiffness

Aortic stiffness, endothelial dysfunction and diastolic dysfunction (DD) are cardiovascular (CV) abnormalities seen in obesity associated with consumption of high fat/fructose western diet (WD). Moreover, CV dysfunction is increasingly prevalent in obese women. Herein, we examined whether the DPP-4 inhibitor, linagliptin (LINA), improves these outcomes in WD fed female C57BL/6 mice. Four week old mice were fed control diet (CD) or WD with or without LINA for 16 weeks, after which pulse wave velocity (aortic stiffness) (PWV), echocardiography (diastolic function), atomic force microscopy (endothelial stiffness) and wire myography (aortic vascular reactivity) were performed. Compared to CD mice, WD mice exhibited 21% and 353% higher PWV and endothelial stiffness, respectively. WD induced DD, indicated by impaired septal wall motion (<E’/A’ ratio), left atrial filling pressure (>E/Vp ratio), prolonged isovolumic relaxation time (IVRT) and impaired myocardial performance index (>MPI). These vascular and cardiac abnormalities were prevented by LINA. LINA also prevented WD-induced impairments in acetylcholine-, sodium nitroprusside-, and insulin-mediated aortic vascular relaxation. These results show that LINA exerts CV protection in a translational model of obesity.

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Abstract P068: Endothelial Mineralocorticoid Receptor Activation Promotes Endothelial And Vascular Stiffening In Western Diet Fed Female Mice Through Sgk1 Mediated Activation Of The Endothelial Sodium Channel

Hypertension ◽

10.1161/hyp.76.suppl_1.p068 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Yan Yang ◽

Zhe Sun ◽

Annayya Aroor ◽

Liping Zhang ◽

Guanghong Jia ◽

...

Keyword(s):

Sodium Channel ◽

Mineralocorticoid Receptor ◽

Sodium Current ◽

Receptor Activation ◽

Western Diet ◽

Vascular Stiffness ◽

Female Mice ◽

Isolated Lung ◽

Vascular Stiffening ◽

Endothelial Stiffness

Over-nutrition/obesity predisposes persons, particularly women, to endothelial dysfunction and vascular stiffening. We have employed a clinically relevant model using female mice fed a high fat and high fructose diet (western diet, WD). These mice display high plasma aldosterone levels, endothelial stiffness and dysfunction and increased mineralocorticoid receptor (MR) expression in the vasculature. One potential mechanism by which MR activation may promote endothelial stiffness is through increased expression and activation of epithelial sodium channel (EnNaC) in endothelial cells (ECs) through mTOR2 mediated activation of serum and glucocorticoid regulated kinase 1(SGK1). In this investigation we observed that WD feeding in female mice for 16 wks caused endothelial (atomic force microscopy (AFM)), and aortic stiffening (PW analysis) in concert with increased expression of EnNaC and SGK1 in the endothelium and EnNaC activation in ECs. Further, amelioration of WD induced EC and vascular stiffness was accomplished by EnNaC inhibition with low dose amiloride (1mg/kg/day in drinking water) over the 16 wks of WD. We then explored the idea that inhibition of SGK1 as well as specific deletion of ECMR and EnNaC decreases vascular EC stiffness accompanied by decreased sodium current in isolated lung ECs. Accordingly, female wild type and ECMR and EnNaC KO mice were fed a WD or control diet (CD) for 16 wks. Aortic and coronary artery EC stiffness, measured ex vivo by AFM, was increased in WD fed mice and this was prevented in ECMR and EnNaC KO models. Both ECMR and EnNaC KO mice fed a WD showed decreased amiloride sensitive sodium current in isolated ECs. Further, in cultured ECs , inhibition of SGK1 by a chemical inhibitor attenuated aldosterone mediated sodium currents. Collectively, these findings support the notion that a WD promotes ECMR mediated increases in SGK1 and associated EnNaC activity in ECs together with increased endothelial and vascular stiffness in females.

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