Heterogeneity of endothelium in human aorta A quantitative analysis by scanning electron microscopy

Repin, V. S.; Dolgov, V V; Zaikina, O.E.; Novikov, I. D.; Antonov, Alexander S.; Nikolaeva, M. A.; Смирнов, В. Н.

doi:10.1016/0021-9150(84)90006-6

Cited by 73 publications

(39 citation statements)

References 14 publications

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“…Several studies have identified SA-β-gal-positive [22][23][24] or giant, multinucleated endothelial cells (ECs) overlying atherosclerotic plaques. [25][26][27][28] EC senescence can be induced in arteries by repeated injury (presumably through replicative exhaustion) 29 and in response to various proatherogenic factors including tumor necrosis factor-α, reactive oxygen species, oxidized low-density lipoprotein, and angiotensin II. 3,4,[30][31][32] By contrast, growth factors 33,34 and NO 22,35 protect ECs from entering the senescent state.…”

Section: Arterioscler Thromb Vasc Biolmentioning

confidence: 99%

Disturbed Flow Promotes Endothelial Senescence via a p53-Dependent Pathway

Warboys

Luca

Amini

et al. 2014

ATVB

180

154

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A ging is a major risk factor for the development of cardiovascular disease, and age-related changes in vascular function are hypothesized to influence the progression of atherosclerosis. One of the hallmarks of aging tissues is an impaired ability to regenerate, caused by the accumulation of senescent cells. Cellular senescence is a state of irreversible growth arrest 1 that can be triggered via the progressive shortening of telomeres (DNA sequence repeats that protect the ends of chromosomes) with successive rounds of cell division, known as replicative senescence.2 Senescence can also be induced by a variety of cellular stresses, independently of extensive proliferation, including oxidative stress 3,4 and activation of oncogenes. 5The signaling pathways that promote cellular senescence vary according to the initiating stimulus, cellular context, and other factors. Senescence can be induced by p16 INK4A (p16) and p14 ARF /p53 signaling pathways.5-8 p16 inhibits cyclin-dependent kinases 2 and 4, whereas p53 induces the cyclin-dependent © 2014 American Heart Association, Inc. Objective-Although atherosclerosis is associated with systemic risk factors such as age, high cholesterol, and obesity, plaque formation occurs predominately at branches and bends that are exposed to disturbed patterns of blood flow. The molecular mechanisms that link disturbed flow-generated mechanical forces with arterial injury are uncertain. To illuminate them, we investigated the effects of flow on endothelial cell (EC) senescence. Approach and Results-LDLR−/− (low-density lipoprotein receptor −/− ) mice were exposed to a high-fat diet for 2 to 12 weeks (or to a normal chow diet as a control) before the assessment of cellular senescence in aortic ECs. En face staining revealed that senescence-associated β-galactosidase activity and p53 expression were elevated in ECs at sites of disturbed flow in response to a high-fat diet. By contrast, ECs exposed to undisturbed flow did not express senescence-associated β-galactosidase or p53. Studies of aortae from healthy pigs (aged 6 months) also revealed enhanced senescence-associated β-galactosidase staining at sites of disturbed flow. These data suggest that senescent ECs accumulate at disturbed flow sites during atherogenesis. We used in vitro flow systems to examine whether a causal relationship exists between flow and EC senescence. Exposure of cultured ECs to flow (using either an orbital shaker or a syringe-pump flow bioreactor) revealed that disturbed flow promoted EC senescence compared with static conditions, whereas undisturbed flow reduced senescence. Gene silencing studies demonstrated that disturbed flow induced EC senescence via a p53-p21 signaling pathway. Disturbed flow-induced senescent ECs exhibited reduced migration compared with nonsenescent ECs in a scratch wound closure assay, and thus may be defective for arterial repair. However, pharmacological activation of sirtuin 1 (using resveratrol or SRT1720) protected ECs from disturbed flow-induced senescence. Conclusions-Distu...

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Section: Arterioscler Thromb Vasc Biolmentioning

confidence: 99%

Disturbed Flow Promotes Endothelial Senescence via a p53-Dependent Pathway

Warboys

Luca

Amini

et al. 2014

ATVB

180

154

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“…A possible link between replicative senescence and atherosclerosis has been inferred from studies in progeroid syndromes. 31,32 Morphological studies [12][13][14] and telomere length analysis 15 in normal individuals have also suggested the presence of senescent ECs covering the surface of atherosclerotic lesions at various stages of disease progression. Furthermore, senescent ECs overexpress in vitro certain proatherogenic and prothrombotic molecules.…”

Section: Discussionmentioning

confidence: 99%

“…6 In contrast, in tissues such as the blood vessel wall, for which the rates of cell turnover are lower, 7,8 the suggestion that senescent cells might accumulate in vivo has remained controversial. 9 -11 Furthermore, although circumstantial evidence points to the accumulation of senescent cells in pathological conditions involving endothelial and vascular smooth muscle cell proliferation, [12][13][14][15][16][17] a definitive demonstration of this phenomenon in vivo is still lacking.…”

mentioning

confidence: 99%

Cellular Senescence After Single and Repeated Balloon Catheter Denudations of Rabbit Carotid Arteries

Fenton

Barker

Kurz

et al. 2001

ATVB

141

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Abstract-The hypothesis that increased cellular proliferation in the vasculature may lead to replicative senescence has been tested in a model of neointima formation. We have used a biomarker of replicative senescence, senescenceassociated ␤-galactosidase (SA-␤-gal), to detect senescence in rabbit carotid arteries subjected to single and double balloon denudations. We found an accumulation of senescent cells in the neointima and media of all injured vessels, in contrast to the near absence of such cells in control vessels. The relative area occupied by SA-␤-gal-positive cells was higher in vessels subjected to double denudation than in those subjected to single denudation, both in the neointima (0.99% versus 0.06%, respectively; PϽ0.001) and in the media (0.11% versus 0.01%, respectively; PϽ0.02). The majority of SA-␤-gal-positive cells were vascular smooth muscle cells, and a minority were endothelial cells. SA-␤-gal-positive cells showed no evidence of apoptosis by use of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling. Our results indicate that the proliferative response that follows intraluminal injury to the artery leads to the emergence of senescent endothelial and smooth muscle cells. The demonstration that vascular cell senescence can occur in vivo suggests that this process may be involved in cardiovascular pathologies that have a proliferative component. for proliferation, a property that is classically manifested on serial passage in culture. 1,2 When this potential is exhausted, cells enter into a permanent nondividing state referred to as replicative senescence. [1][2][3][4] It has been postulated that this process may also occur in vivo in tissues in which cell proliferation continues throughout the entire lifespan of the organism. 2 Furthermore, it has been suggested that replicative senescence may contribute to aging of the individual and to the development of age-related diseases. 2,5 In tissues such as skin, for which the rates of cell turnover are relatively high, the presence of senescent cells has been confirmed. 6 In contrast, in tissues such as the blood vessel wall, for which the rates of cell turnover are lower, 7,8 the suggestion that senescent cells might accumulate in vivo has remained controversial. 9 -11 Furthermore, although circumstantial evidence points to the accumulation of senescent cells in pathological conditions involving endothelial and vascular smooth muscle cell proliferation, 12-17 a definitive demonstration of this phenomenon in vivo is still lacking.Until recently, the putative identification of individual senescent cells has had to rely mainly on morphological examination. This situation has changed with the discovery that a cytochemical assay of ␤-galactosidase can be used to detect senescent cells selectively if the reaction is performed at pH 6.0. 6 This endogenous pH 6.0 activity has been termed senescence-associated ␤-galactosidase (SA-␤-gal). 6 Initially, SA-␤-gal was found in senescent cultures of fibroblasts, 6 keratinocytes, 6 and epith...

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“…16 In addition to undergoing proliferation, some endothelial cells enlarge to nearly twice normal size and resemble multinucleated giant endothelial cells located over atherosclerotic plaques. 50,51 Giant endothelial cells in the airway microvasculature may be a manifestation of rapid proliferation, but they are unlikely to play a major role in increased vessel caliber because they were infrequent and their presence was limited to the period of most rapid endothelial cell proliferation.…”

Section: Change In Endothelial Cell Phenotypementioning

confidence: 99%

Time Course of Endothelial Cell Proliferation and Microvascular Remodeling in Chronic Inflammation

Ezaki

Bałuk

Thurston

et al. 2001

The American Journal of Pathology

118

115

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Angiogenesis and vascular remodeling are features of many chronic inflammatory diseases. When diseases evolve slowly, the accompanying changes in the microvasculature would seem to be similarly gradual. Here we report that the rate of endothelial cell proliferation and the size of blood vessels increases rapidly after the onset of an infection that leads to chronic inflammatory airway disease. In C3H mice inoculated with Mycoplasma pulmonis, the tracheal microvasculature, made visible by perfusion of Lycopersicon esculentum lectin, rapidly enlarged from 4 to 7 days after infection and then plateaued. Diameters of arterioles, capillaries, and venules increased on average 148, 214, and 74%, respectively. Endothelial cell proliferation, measured by bromodeoxyuridine (BrdU) labeling, peaked at 5 days (18 times the pathogen-free value), declined sharply until day 9, but remained at ϳ3 times the pathogen-free value for at least 28 days. Remodeled capillaries and venules were sites of focal plasma leakage and extensive leukocyte adherence. Most systemic manifestations of the infection occurred well after the peak of endothelial proliferation, and the humoral immune response to M. pulmonis was among the latest, increasing after 14 days. These data show that endothelial cell proliferation and microvascular remodeling occur at an early stage of chronic airway disease and suggest that the vascular changes precede widespread tissue remodeling. Angiogenesis and vascular remodeling are important elements of the pathophysiology of cancer and chronic inflammatory diseases and may be essential for the persistence of these conditions. 1 The vasculature provides metabolic support for the diseased tissues and serves as the gatekeeper for incoming inflammatory cells and outgoing tumor cells that form metastases. The recognition that newly formed and remodeled vessels are different from those normally present led to the identification of probes to target diseased vessels selectively 2,3 and to the use of angiogenesis inhibitors in the treatment of cancer and chronic inflammation. 1,4 The properties and functional implications of angiogenic blood vessels have been examined in many animal models of cancer, 5-8 but less is known about the vascular changes in chronic inflammation. One might expect the microvasculature to change gradually as protracted inflammatory diseases evolve, or it could change rapidly at the beginning and drive other aspects of the disease. Yet the time course of changes in the vasculature in chronic inflammation has not been addressed systematically, in part because of limited suitable animal models.One animal model that has been useful for studying angiogenesis and vascular remodeling in chronic inflammation is the respiratory tract infection caused by Mycoplasma pulmonis in mice and rats. This infection causes severe, lifelong changes in the microvasculature of the airway mucosa, 9 -11 along with extensive tissue remodeling, leukocyte influx, epithelial and gland hyperplasia, and fibrosis in the airways and, in ...

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Heterogeneity of endothelium in human aorta A quantitative analysis by scanning electron microscopy

Cited by 73 publications

References 14 publications

Disturbed Flow Promotes Endothelial Senescence via a p53-Dependent Pathway

Disturbed Flow Promotes Endothelial Senescence via a p53-Dependent Pathway

Cellular Senescence After Single and Repeated Balloon Catheter Denudations of Rabbit Carotid Arteries

Time Course of Endothelial Cell Proliferation and Microvascular Remodeling in Chronic Inflammation

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