Adaptation to arterial wall hypoxia demonstrated in vivo with oxygen microcathodes

Zemplenyi, T; Crawford, Donald W.; Cole, Mark A.

doi:10.1016/0021-9150(89)90101-9

Cited by 64 publications

(46 citation statements)

References 21 publications

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“…The anoxemia theory of atherosclerosis was first suggested by Heuper in 1944 (42). Subsequently, in vitro and in situ studies found reduced pO 2 levels in the arterial walls of animals with atherosclerosis (43,44). The in vivo evidence of arterial wall hypoxia has only recently been demonstrated in an experimental model of atherosclerosis (12).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Stimulates Osteopontin Expression and Proliferation of Cultured Vascular Smooth Muscle Cells

et al. 2001

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We examined the effect of hypoxia on proliferation and osteopontin (OPN) expression in cultured rat aortic vascular smooth muscle (VSM) cells. In addition, we determined whether hypoxia-induced increases in OPN and cell proliferation are altered under hyperglycemic conditions. Quiescent cultures of VSM cells were exposed to hypoxia (3% O 2 ) or normoxia (18% O 2 ) in a serum-free medium, and cell proliferation as well as the expression of OPN was assessed. Cells exposed to hypoxia for 24 h exhibited a significant increase in [ 3 H]thymidine incorporation followed by a significant increase in cell number at 48 h in comparison with respective normoxic controls. Exposure to hypoxia produced significant increases in OPN protein and mRNA expression at 2 h followed by a gradual decline at 6 and 12 h, with subsequent significant increases at 24 h. Neutralizing antibodies to either OPN or its receptor ␤3 integrin but not neutralizing antibodies to ␤5 integrin prevented the hypoxia-induced increase in T he first descriptions of a link between systemic hypoxia and pulmonary artery smooth muscle cell proliferation came from both in vivo and in vitro models of pulmonary hypertension (1-3). Increased proliferation of aortic vascular smooth muscle (VSM) cells is also a key feature in the progression of atherosclerosis (4). Both systemic and local hypoxia contributes to the development of atherosclerotic lesions (5-11). Recent in vivo studies found a direct correlation of local arterial wall hypoxia, VSM cell proliferation, and atherosclerosis (12,13). However, the underlying signaling mechanisms whereby hypoxia induces VSM cell proliferation and subsequent atherosclerotic lesions remain poorly defined. Part of the problem has been in the demonstration of a mitogenic effect of hypoxia in cultured VSM cells in vitro. Hypoxia has only been shown to induce the proliferation of bovine pulmonary artery smooth muscle cells in culture when they are costimulated either with an activator of protein kinase C (PKC) or serum (3,14). To examine the effect of local hypoxia on cell proliferation, our laboratory has developed an appropriate cell culture model system in which cultured cells exhibited differentiated morphology and function by improved oxygenation (15). Using this culture model, we reported that hypoxia induces proliferation, dedifferentiation, and/or extracellular matrix synthesis in cultured renal tubular epithelial and glomerular mesangial cells (16 -18). In the present study, we examined the effect of hypoxia on the proliferation of cultured rat aortic VSM cells to determine whether hypoxia directly alters their proliferative behavior.Enhanced proliferation of VSM cells has also been demonstrated in both human and experimental models of diabetes (19,20). In addition, cultured VSM cells grown in high media glucose concentration (to mimic hyperglycemia of diabetes) have exhibited increased cell proliferation (21). The pathophysiological mechanisms responsible for accelerated VSM cell proliferation and progression into diabetic...

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Section: Discussionmentioning

confidence: 99%

Hypoxia Stimulates Osteopontin Expression and Proliferation of Cultured Vascular Smooth Muscle Cells

et al. 2001

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“…54 TNF-␣ can increase Sp-1-mediated VEGF expression also. 55 Therefore, hypoxia in the deeper 56 and cell-rich sites of atherosclerotic intimas 57 and proinflammatory cytokines such as TNF-␣ and IL-1␤ may also play a role in VEGF overexpression in atherosclerotic intimas.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical Expression of Vascular Endothelial Growth Factor/Vascular Permeability Factor in Atherosclerotic Intimas of Human Coronary Arteries

Chen

Nakashima

Tanaka

et al. 1999

ATVB

108

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Abstract-Neovascularization is well known to occur in human atherosclerotic plaques; however, its pathophysiological roles, mechanisms, and stimuli in atherogenesis still remain unclear. In this study, 525 tissue blocks of coronary artery tissue obtained at autopsy from 48 patients ranging in age from 20 to 93 years old (meanϮSD, 71Ϯ15 years) were immunohistochemically examined for vascular endothelial growth factor (VEGF) expression in the atherosclerotic intimas. The atherosclerotic lesions were histopathologically classified into types I through VI, as proposed by the American Heart Association Committee, and the numbers of intimal blood vessels and VEGF-positive cells were then morphometrically counted in sections that were immunohistochemically examined with anti-CD34 and human VEGF antibodies, respectively. The more the atherosclerotic lesion type advanced, the more often the lesion contained intimal blood vessels, which were expressed as percentages of the intimal section with intimal microvessels, viz, diffuse intimal thickening (

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“…A decrease in arterial wall oxygenation attributable to atherosclerosis, 25,26 hypertension, 27 or hypercholesterolemia 28 leads to a compensatory increase in the number of adventitial vasa vasorum. This increases tissue perfusion and counteracts the development of arterial wall hypoxia in vivo.…”

Section: Energy Metabolism Under Hypoxiamentioning

confidence: 99%

“…This increases tissue perfusion and counteracts the development of arterial wall hypoxia in vivo. 25 However, there seem to be a limit for this compensatory mechanism, because the core of rabbit atherosclerotic plaques is severely hypoxic in vivo when the intimal thickness exceeds 300 m. 15 This failure to adequately increase tissue perfusion might be explained by the more irregular growth pattern and poorly supported wall of the newly formed vasa vasorum. 26,28 …”

Section: Energy Metabolism Under Hypoxiamentioning

confidence: 99%

Mapping of ATP, Glucose, Glycogen, and Lactate Concentrations Within the Arterial Wall

Levin

Leppänen

Evaldsson

et al. 2003

ATVB

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Objective-In large-and medium-sized arteries, the diffusion distances for oxygen and nutrients are long. This has been suggested to make these vessels prone to develop local energy metabolic deficiencies that could contribute to atherogenesis. To validate this hypothesis, we introduced a new method to measure energy metabolites within the arterial wall at high spatial resolution. Methods and Results-Bioluminescence imaging was used to quantify local metabolite concentrations in cryosections of snap frozen (in vivo) and incubated pig carotid artery rings. Incubation at hypoxia resulted in increased lactate concentrations, whereas ATP, glucose, and glycogen concentrations were decreased, especially in the mid media, where concentrations of these metabolites were close to zero. In snap frozen arteries, glycogen concentrations were markedly higher in deep layers of the media than toward the lumen. ATP, glucose, and lactate were more homogenously distributed. Key Words: atherosclerosis Ⅲ hypoxia Ⅲ bioluminescence Ⅲ energy metabolism Ⅲ imaging T he arterial wall is supplied with oxygen and nutrients by diffusion and convection from luminal blood and from vasa vasorum in the adventitia and outer media. Metabolic waste products are removed by diffusion in the opposite direction. Diffusion distances in large-and medium-sized arteries are often close to, or even exceed, the 100 to 200 m that is frequently stated as the diffusion limit for oxygen. 1-4 Based on these facts, it has been suggested that the arterial wall is predisposed to develop local energy metabolic disturbances and that this is a key factor both in the initiation and progression of atherosclerosis. 1 In atherosclerosis-prone areas, both insufficient transport 5,6 and increased consumption of metabolites 7 could contribute to local disturbances. Later in the disease process, increased diffusion distances, attributable to intimal thickening as well as a high consumption of oxygen 8 and glucose 9,10 by foam cells, could additionally aggravate energy metabolic predicaments and contribute to the development of a necrotic core. Supportive of this hypothesis, hypoxic zones have been demonstrated in situ in the normal pig arterial wall 11 as well as in vitro 12-14 and in vivo 15 in rabbit atherosclerotic plaques. However, ATP production may be maintained under hypoxic conditions via anaerobic breakdown of glucose and glycogen, but this could lead to a potentially harmful accumulation of lactate. Therefore, other aspects of energy metabolism besides the supply of oxygen need to be analyzed. To the best of our knowledge, bioluminescence imaging is the only method available that allows analysis of ATP, glucose, and lactate concentrations at the necessary spatial resolution. 16 We have recently adapted this method to measure local ATP concentrations within the arterial wall. 14 In the present study, our methodology is extended to include determinations of glucose, glycogen, and lactate. The use of bioluminescence imaging to measure glycogen concentrations is presented...

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Adaptation to arterial wall hypoxia demonstrated in vivo with oxygen microcathodes

Cited by 64 publications

References 21 publications

Hypoxia Stimulates Osteopontin Expression and Proliferation of Cultured Vascular Smooth Muscle Cells

Hypoxia Stimulates Osteopontin Expression and Proliferation of Cultured Vascular Smooth Muscle Cells

Immunohistochemical Expression of Vascular Endothelial Growth Factor/Vascular Permeability Factor in Atherosclerotic Intimas of Human Coronary Arteries

Mapping of ATP, Glucose, Glycogen, and Lactate Concentrations Within the Arterial Wall

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