Targets for regulating angiogenesis in the ageing endothelium

Ballard, Victoria L. T.; Edelberg, Jay M.

doi:10.1517/14728222.11.11.1385

Cited by 14 publications

(6 citation statements)

References 120 publications

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“…This is compatible with the reported antiangiogenic effect of S-endoglin in contrast to the proangiogenic role attributed to L-endoglin. 12,26,31 Interestingly, angiogenic function is progressively impaired with increasing age, 32 which fits well with the upregulation of S-endoglin in senescent ECs and its antiangiogenic effect. This short endoglin isoform is able to exert opposite effects to that of the predominantly expressed L-endoglin on the TGF-␤ signal, including the positive and negative cooperation with ALK5 and ALK1, respectively.…”

Section: Blanco Et Al S-endoglin In Senescent Endothelial Cellsmentioning

confidence: 72%

S-Endoglin Expression Is Induced in Senescent Endothelial Cells and Contributes to Vascular Pathology

Blanco¹,

Grande²,

Langa³

et al. 2008

Circulation Research

119

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Abstract-Senescence of endothelial cells (ECs) may contribute to age-associated cardiovascular diseases, including atherosclerosis and hypertension. The functional and gene expression changes associated with cellular senescence are poorly understood. Here, we have analyzed the expression, during EC senescence, of 2 different isoforms (L, long; S, short) of endoglin, an auxiliary transforming growth factor (TGF)-␤ receptor involved in vascular remodeling and angiogenesis. As evidenced by RT-PCR, the S/L ratio of endoglin isoforms was increased during senescence of human ECs in vitro, as well as during aging of mice in vascularized tissues. Next, the effect of S-endoglin protein on the TGF-␤ receptor complex was studied. As revealed by coimmunoprecipitation assays, S-endoglin was able to interact with both TGF-␤ type I receptors, ALK5 and ALK1, although the interaction with ALK5 was stronger than with ALK1. S-endoglin conferred a lower proliferation rate to ECs and behaved differently from L-endoglin in relation to TGF-␤-responsive reporters with ALK1 or ALK5 specificities, mimicking the behavior of the endothelial senescence markers Id1 and plasminogen activator inhibitor-1. In situ hybridization studies demonstrated the expression of S-endoglin in the endothelium from human arteries. Transgenic mice overexpressing S-endoglin in ECs showed hypertension, decreased hypertensive response to NO inhibition, decreased vasodilatory response to TGF-␤ 1 administration, and decreased endothelial nitric oxide synthase expression in lungs and kidneys, supporting the involvement of S-endoglin in the NO-dependent vascular homeostasis. Taken together, these results suggest that S-endoglin is induced during endothelial senescence and may contribute to age-dependent vascular pathology. Key Words: endothelial cells Ⅲ hypertension Ⅲ TGF-␤ receptors Ⅲ aging Ⅲ endoglin C ardiovascular repair mechanisms become progressively impaired with age, and advanced age is itself a significant risk factor for cardiovascular disease. 1 Defects in age-associated remodeling of the vascular wall are, in part, attributable to the declining of endothelial function. 2,3 Thus, vascular processes such as angiogenesis, nutrient trafficking, vascular repair, and homeostasis are impaired because of attenuation of endothelial cell (EC) proliferation, migration, or dilator responses. EC proliferation diminishes with age, entering in an irreversible senescent state. 4 Senescent cells undergo growth arrest in the G 1 phase and a change in morphology and metabolism. Some of the senescence-associated changes include cellular enlargement, altered response to growth factors such as transforming growth factor (TGF)-␤ 1 , and expression of senescence-associated ␤-galactosidase (SA-␤-gal). 5 Also, alterations in the expression and/or activity of the endothelial nitric oxide synthase (eNOS) are critical for the attenuation of the endothelium-dependent dilatory responses with age. 6,7 Unfortunately, most of the functional and gene expression changes associated with...

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Section: Blanco Et Al S-endoglin In Senescent Endothelial Cellsmentioning

confidence: 72%

S-Endoglin Expression Is Induced in Senescent Endothelial Cells and Contributes to Vascular Pathology

Blanco¹,

Grande²,

Langa³

et al. 2008

Circulation Research

119

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“…Angiogenic function is progressively impaired with increasing age and impaired angiogenic function has been linked to the development and progression of a variety of pathological conditions including cancer and CVDs [25]. For example, the formation of new blood vessels has been observed in the atherosclerotic plaques of human coronary arteries and the number of new vessels was shown to correlate with the degree of inflammation and severity of the lesion [26].…”

Section: Discussionmentioning

confidence: 99%

Oligomeric procyanidins inhibit cell migration and modulate the expression of migration and proliferation associated genes in human umbilical vascular endothelial cells

García‐Conesa

Tribolo

Guyot

et al. 2009

Molecular Nutrition Food Res

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The consumption of flavan-3-ols has been associated with reduced risk of cardiovascular diseases and improvements in vascular function. However, the nature of the flavan-3-ols responsible and the mechanisms underlying the vascular responses are not fully understood. We used microarrays to search for molecular changes in response to the exposure to (-)-epicatechin (EC), procyanidin dimer B2, and a mixture of oligomeric procyanidins in human umbilical vein endothelial cells (HUVECs). No gene expression changes were detected in HUVECs exposed to EC or dimer B2, however, the oligomeric procyanidins induced significant gene expression changes in both resting and TNF-alpha-stimulated cells. In particular, the expression of genes such as ADAMTS1, THBS1, ANGPT2, CYR61, ET-1, EDG3, and PDE4B involved in endothelial cell migration and proliferation, were substantially over-represented. Also, exposure to the oligomers arrested the cells at the G(0)/G(1 )phase and inhibited cell migration. These data show that human endothelial cells respond to oligomeric procyanidins by exhibiting a less migratory phenotype and by a general modulation of the expression of genes that are associated with key events in the angiogenic process. The molecular changes associated with procyanidin treatment identified in this study are consistent with the beneficial effects of flavan-3-ols on vascular function.

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“…This endothelial reconstruction can be accomplished by the proliferation and migration of surrounding mature endothelial cells [1,2]. However, mature endothelial cells are terminally differentiated cells with low proliferative potential, and their capacity to repair damaged vessels is limited [3,4]. Recent studies reveal that endothelial progenitor cells (EPCs) which reside in the bone marrow and to some extent in peripheral blood [5,6], play an important role in angiogenesis through their capacity to proliferate, migrate, differentiate and as a source of paracrine factors for pro-angiogenic cytokines [7,8].…”

Section: Introductionmentioning

confidence: 99%

Comparison of endothelial progenitor cell function in type 2 diabetes with good and poor glycemic control

et al. 2010

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BackgroundEndothelial progenitor cells (EPCs) play an important role in vascular repair and a decrease in the number of EPCs is observed in type 2 diabetes. However, there is no report on the change of EPCs after glycemic control. This study therefore aimed to investigate the EPC number and function in patients with good and poor glycemic control.MethodsThe number of EPCs was studied using flow cytometry by co-expression of CD34 and VEGFR2. The EPCs were cultured and characterized by the expression of UEA-I, CD34, VEGFR2, vWF and Dil-Ac-LDL engulfment, as well as the ability to form capillary-like structures. An in vitro study on the effect of hyperglycemia on the proliferation and viability of the cultured EPCs was also performed.ResultsThe number of EPCs in type 2 diabetes was significantly decreased compared with healthy controls and there was an inverse correlation between the EPC numbers and plasma glucose, as well as HbA1C. The number and function of EPCs in patients with good glycemic control were recovered compared with those with poor glycemic control. When glucose was supplemented in the culture in vitro, there was a negative effect on the proliferation and viability of EPCs, in a dose-dependent manner, whereas the enhancement of apoptosis was observed.ConclusionThere was EPC dysfunction in type 2 diabetes which might be improved by strict glycemic control. However, the circulating EPC number and proliferative function in patients with good glycemic control did not reach the level in healthy controls.

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Targets for regulating angiogenesis in the ageing endothelium

Cited by 14 publications

References 120 publications

S-Endoglin Expression Is Induced in Senescent Endothelial Cells and Contributes to Vascular Pathology

S-Endoglin Expression Is Induced in Senescent Endothelial Cells and Contributes to Vascular Pathology

Oligomeric procyanidins inhibit cell migration and modulate the expression of migration and proliferation associated genes in human umbilical vascular endothelial cells

Comparison of endothelial progenitor cell function in type 2 diabetes with good and poor glycemic control

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