Hypertension, Arterial Stiffness, and Clinical Outcomes: A Cohort Study of Chinese Community-Based Population.

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CXCR7 upregulation is required for early endothelial progenitor cell-mediated endothelial repair in patients with hypertension.

Dysfunction of early endothelial progenitor cells (EPCs) is responsible for impaired endothelial repair capacity after arterial injury in patients with hypertension. Here, we hypothesized that diminished signaling of CXC chemokine receptor 7 (CXCR7) contributes to the reduced EPC functions, and enhanced CXCR7 expression restores the capacities of EPCs from hypertensive patients. CXCR7 expression of EPCs from hypertensive patients was significantly reduced when compared with that from healthy subjects. Meanwhile, the phosphorylation of p38 mitogen-activated protein kinase, a downstream signaling of CXCR7, was elevated, which increased cleaved caspase-3 level of EPCs. CXCR7 gene transfer augmented CXCR7 expression and decreased the phosphorylation of p38 mitogen-activated protein kinase, which was paralleled to EPC functional upregulation of in vitro adhesion, antiapoptosis activities, and in vivo re-endothelialization capacity in a nude mouse model of carotid artery injury. The enhanced in vitro and in vivo functions of EPCs were markedly inhibited by neutralizing monoclonal antibody against CXCR7, which was blocked by p38 mitogen-activated protein kinase inhibitor SB203580. Downregulation of cleaved caspase-3 level induced by CXCR7 gene transfer or SB203580 pretreatment improved EPC functions. Furthermore, we found that lercanidipine, a dihydropyridine calcium channel antagonist, enhanced CXCR7 expression and facilitated in vitro and in vivo functions of EPCs. Our study demonstrated for the first time that diminished CXCR7 signal at least partially contributes to the reduced in vitro functions and in vivo re-endothelialization capacity of EPCs from hypertensive patients. Upregulation of CXCR7 expression induced by gene transfer or lercanidipine treatment may be a novel therapeutic target for increased endothelial repair capacity in hypertension.

Lacidipine improves endothelial repair capacity of endothelial progenitor cells from patients with essential hypertension.

BACKGROUND: Endothelial progenitor cells (EPCs) play a critical role in maintaining the integrity of vascular endothelium following arterial injury. Lacidipine has a beneficial effect on endothelium of hypertensive patients, but limited data are available on EPCs-mediated endothelial protection. This study tests the hypothesis that lacidipine treatment can improve endothelial repair capacity of EPCs from hypertensive patients through increasing CXC chemokine receptor four (CXCR4) signaling. METHODS: In vivo reendothelialization capacity of EPCs from hypertensive patients with or without in vitro lacidipine treatment was examined in a nude mouse model of carotid artery injury. Expression of CXCR4 and alteration in migration and adhesion functions of EPCs were evaluated. RESULTS: Basal CXCR4 expression was markedly reduced in EPCs from hypertensive patients compared with normal subjects. In parallel, the phosphorylation of Janus kinase-2 (JAK-2) of EPCs, a CXCR4 downstream signaling, was also significantly decreased. Lacidipine promoted CXCR4/JAK-2 signaling expression of in vitro EPCs. Transplantation of EPCs pretreated with lacidipine significantly accelerated in vivo reendothelialization. The enhanced in vitro function and in vivo reendothelialization capacity of EPCs were inhibited by shRNA-mediated knockdown of CXCR4 expression or pretreatment with JAK-2 inhibitor AG490, respectively. In hypertensive patients, lacidipine treatment for 4 weeks also resulted in an upregulation of CXCR4/JAK-2 signaling of EPCs, which was associated with augmented EPCs-mediated reendothelialization and improved endothelial function. CONCLUSION: Deterioration of CXCR4 signaling may lead to impaired EPCs-mediated reendothelialization of hypertensive patients. Lacidipine-modified EPCs via a partially CXCR4 signaling contribute to enhanced endothelial repair capacity in hypertension.

Regular exercise-induced increased number and activity of circulating endothelial progenitor cells attenuates age-related decline in arterial elasticity in healthy men.

BACKGROUND: Deficiency in number and activity of circulating EPCs is associated with reduced arterial elasticity in humans with advancing aging. Physical exercise can increase the number and activity of circulating EPCs in humans. Here we investigated whether regular exercise-induced enhanced circulating endothelial progenitor cells (EPCs) improves age-related decline in arterial elasticity in healthy men. METHODS: In a cross-sectional study, the number and activity of circulating EPCs as well as brachial-ankle pulse wave velocity (baPWV) of young and older sedentary or endurance-trained healthy men were studied. Then we observed the effect of regular exercise on circulating EPCs and baPWV of 10 older and 10 young sedentary healthy men. RESULTS: In both sedentary and endurance-trained men, the number and activity of circulating EPCs were significantly low in older men compared with young men, which was paralleled to increased baPWV. After three months of regular exercise, the number and activity of circulating EPCs increased, and the baPWV of 10 older and 10 young sedentary healthy men decreased. However, the increased number and activity of circulating EPCs and decreased baPWV of older sedentary healthy men were higher. There was a close correlation between circulating EPCs and baPWV. Multivariate analysis identified proliferative activity of circulating EPCs as an independent predictor of baPWV. CONCLUSIONS: The present study demonstrates for the first time that regular physical exercise-induced enhanced circulating EPCs attenuates age-related decline in arterial elasticity in healthy men. These findings provide novel insights into the protective effects of exercise on age-related vascular injury.

Age-related decline in reendothelialization capacity of human endothelial progenitor cells is restored by shear stress.

Aging is associated with dysfunction of endothelial progenitor cells (EPCs), and shear stress has a beneficial impact on EPC function; however, the effects of aging and shear stress on the endothelial repair capacity of EPCs after arterial injury have not been reported. Here we investigated the influence of aging and shear stress on the reendothelialization capacity of human EPCs and the related molecular mechanism. Compared with EPCs isolated from young subjects, EPCs from the elderly displayed an impaired migration and adhesion in vitro and demonstrated a significantly reduced reendothelialization capacity in vivo after transplantation into nude mice with carotid artery denudation injury. Shear stress pretreatment enhances the migration, adhesion, and reendothelialization capacity in both young and elderly EPCs; however, it was to a greater extent in EPCs from the elderly. Although basal CXC chemokine receptor 4 (CXCR4) expression was similar in EPCs from the 2 age groups, the stromal cell derived factor 1-induced CXCR4 and Janus kinase 2 phosphorylations were much lower in the elderly than in young EPCs. Shear stress treatment upregulated CXCR4 expression and phosphorylation and, importantly, restored the stromal cell-derived factor 1/CXCR4-dependent Janus kinase 2 phosphorylation in the elderly EPCs. Furthermore, short hairpin RNA-mediated knockdown of CXCR4 expression or pretreatment with Janus kinase 2 inhibitor diminished the enhancement in the migration, adhesion, and reendothelialization capacity of the elderly EPCs from shear stress treatments. Thus, our study demonstrates that upregulation of the CXCR4/Janus kinase 2 pathway by shear stress contributes to the enhanced reendothelialization capacity of EPCs from elderly men.

Shear stress-induced activation of Tie2-dependent signaling pathway enhances reendothelialization capacity of early endothelial progenitor cells.

Although endothelial progenitor cells (EPCs) play a pivotal role in the endothelial repair following arterial injury and shear stress has a beneficial effect on EPCs, however, the molecular mechanism underlying the influence of EPCs on the endothelial integrity and the regulation of shear stress on the EPC signaling remained to be studied. Here, we investigated the effects of laminar shear stress on the tyrosine kinase with immunoglobulin and epidermal growth factor homology domain-2 (Tie2)-dependent signaling and its relation to in vivo reendothelialization capacity of human early EPCs. The human early EPCs were treated with shear stress. Shear stress in a dose-dependent manner increased angiopoietin-2 (Ang2)-induced migratory, adhesive and proliferatory activities of EPCs. Transplantation of EPCs treated by shear stress facilitated in vivo reendothelialization in nude mouse model of carotid artery injury. In parallel, the phosphorylation of Tie2 and Akt of EPCs in response to shear stress was significantly enhanced. With treatment of Tie2 knockdown or Akt inhibition, shear stress-induced phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) of EPCs was markedly suppressed. After Tie2/PI3K/Akt/eNOS signaling was blocked, the effects of shear stress on in vitro function and in vivo reendothelialization capacity of EPCs were significantly inhibited. The present findings demonstrate for the first time that Tie2/PI3k/Akt/eNOS signaling pathway is, at least in part, involved in the EPCs-mediated reendothelialization after arterial injury. The upregulation of shear stress-induced Tie2-dependent signaling contributes to enhanced in vivo reendothelialization capacity of human EPCs.

Impaired endothelial progenitor cell activity is associated with reduced arterial elasticity in patients with essential hypertension.

Endothelial dysfunction is related to reduced arterial elasticity in patients with essential hypertension. Circulating endothelial progenitor cells (EPCs), an important endogenous repair approach for endothelial injury, is altered in hypertensive patients. However, the association between alteration in circulating EPCs and hypertension-related reduced arterial elasticity has not been reported. The purpose of this study is to investigate the association between alteration in circulating EPCs and hypertension-related reduced arterial elasticity. We measured the artery elasticity profiles including brachial-ankle PWV (baPWV) and C1 large and C2 small artery elasticity indices in patients with essential hypertension (n = 20) and age-matched normotensive subjects (n = 21). The number and activity of circulating EPCs isolated from peripheral blood were determined. Compared to normotensive subjects, the patients with hypertension exhibited decreased C1 large and C2 small artery elasticity indices, as well as increased baPWV. The number of circulating EPCs did not differ between the two groups. The migratory and proliferative activities of circulating EPCs in hypertensive patients were lower than those in normotensive subjects. Both proliferatory and migratory activities of circulating EPCs closely correlated with arterial elasticity profiles, including baPWV and C1 large and C2 small artery elasticity indices. Multivariate analysis identified both proliferative and migratory activities of circulating EPCs as independent predictors of the artery elasticity profiles. The present study demonstrates for the first time that impaired activity of circulating EPCs is associated with reduced arterial elasticity in patients with hypertension. The fall in endogenous repair capacity of vascular endothelium may be involved in the pathogenesis of hypertension-related vascular injury.

CXCR4 gene transfer contributes to in vivo reendothelialization capacity of endothelial progenitor cells.

AIMS: Endothelial progenitor cells (EPCs) play a pivotal role in endothelial repair after artery injury. The chemokine receptor CXCR4 is a key modulator of the homing of EPCs to impaired artery and reendothelialization. In this study, we addressed the hypothesis that CXCR4 gene transfer could enhance the reendothelialization capacity of EPCs. METHODS AND RESULTS: In vitro, human EPCs were expanded and transduced with adenovirus serotype 5 encoding the human CXCR4 gene (Ad5/CXCR4). In vitro, CXCR4 gene transfer augmented EPC migration and enhanced EPC adhesion to endothelial cell monolayers. Adhesion assays under flow conditions showed that CXCR4 gene transfer increased the ability of EPCs to arrest on fibronectin. To determine whether CXCR4 gene transfer facilitated therapeutic reendothelialization, the effect of EPCs on in vivo reendothelialization was examined in nude mice subjected to carotid artery injury. Compared with the vehicle, transplantation of EPCs with or without gene transfer significantly accelerated in vivo reendothelialization; however, transplantation of EPCs transduced with Ad5/CXCR4 had a further enhanced effect compared with control EPCs containing EPCs transduced with an adenovirus encoding enhanced green fluorescent protein gene or non-transduced EPCs. We also found that phosphorylation of Janus kinase-2 (JAK-2), a CXCR4 downstream signalling target, was increased in EPCs transduced with Ad5/CXCR4. The enhanced in vitro function and in vivo reendothelialization capacity of EPCs by CXCR4 gene transfer were abolished by neutralizing antibodies against CXCR4 or/and JAK-2 inhibitor AG490. CONCLUSION: The present study demonstrates that CXCR4 gene transfer contributes to the enhanced in vivo reendothelialization capacity of EPCs. Up-regulation of CXCR4 in human EPCs may become a novel therapeutic target for endothelial repair.