Chronic hypoxia attenuates VEGF signaling and angiogenic responses by downregulation of KDR in human endothelial cells

Olszewska-Pazdrak, Barbara; Hein, Travis W.; Olszewska, Paulina; Carney, Darrell H.

doi:10.1152/ajpcell.00533.2008

Cited by 91 publications

(67 citation statements)

References 55 publications

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“…21,22 A recent report indicated that chronic hypoxia attenuates VEGF signaling and angiogenic responses by downregulation of VEGF receptor 2 in human endothelial cells. 23 We confirmed that VEGF receptor 2 expression in the aging rat kidney was decreased compared with that in young rat kidney. This may provide a novel explanation for impaired angiogenic responses to VEGF in the aging kidney.…”

Section: Discussionsupporting

confidence: 73%

Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney

Satoh

Fujimoto

Horike

et al. 2011

Laboratory Investigation

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Decreased expression of vascular endothelial growth factor (VEGF) in the renal tubules is thought to cause progressive loss of the renal microvasculature with age. Mitochondrial dysfunction may be a principal phenomenon underlying the process of aging. The relation between VEGF expression and mitochondrial dysfunction in aging is not fully understood. We hypothesized that mitochondrial dysfunction blocks VEGF expression and contributes to impaired angiogenesis in the aging kidney. The aim of this study was to assess the role of mitochondria in VEGF expression in the aging rat kidney. We evaluated the accumulation of 8-hydroxy-2 0 -deoxyguanosine in mitochondrial DNA, as well as mitochondrial dysfunction, as assessed by electron microscopy of mitochondrial structure and histochemical staining for respiratory chain complex IV, in aging rat kidney. An increase in hypoxic area and a decrease in peritubular capillaries were detected in the cortex of aging rat kidneys; however, upregulation of VEGF expression was not observed. The expression of VEGF in proximal tubular epithelial cells in response to hypoxia was suppressed by the mitochondrial electron transfer inhibitor myxothiazol. Mitochondrial DNA-deficient cells also failed to upregulate VEGF expression under hypoxic conditions. These results indicate that impairment of VEGF upregulation, possibly as a result of mitochondrial dysfunction, contributes to impaired angiogenesis, which in turn leads to renal injury in the aging rat kidney.

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Section: Discussionsupporting

confidence: 73%

Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney

Satoh

Fujimoto

Horike

et al. 2011

Laboratory Investigation

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“…Studies of VEGFR2 expression in animal models of brain ischemia and in vitro models of neuronal or brain tissue hypoxia have yielded conflicting results. In some, VEGFR2 was upregulated [69][70][71][72][73] and in others, decreased [74][75][76]. Other factors that may account for the reduced or unchanged microvessel density in hyperperfused cortex in AD [3] include sequestration of VEGF by Aβ42 [55], the decreased VEGFR1:sVEGFR1 ratio (see above), and binding of Aβ42 to VEGFR2 -shown by Patel et al [2010] to block VEGF-mediated signaling.…”

Section: Discussionmentioning

confidence: 99%

VEGFR1 and VEGFR2 in Alzheimer’s Disease

Harris

Miners

Allen

et al. 2017

JAD

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Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. Despite upregulation of VEGF in the brain in Alzheimer's disease (AD), probably in response to amyloid-␤, vasoconstriction, and tissue hypoxia, there is no consequent increase in microvessel density. VEGF binds to and activates VEGF receptor 2 (VEGFR2), but also binds to VEGF receptor 1 (VEGFR1), which exists in less-active membrane-bound and inactive soluble (sVEGFR1) forms and inhibits pro-angiogenic signaling. We have investigated whether altered expression of VEGF receptors might account for the lack of angiogenic response to VEGF in AD. We assessed the cellular distribution and protein level of VEGFR1 and VEGFR2 in parietal cortex from 50 AD and 36 age-matched control brains, and related the findings to measurements of VEGF and von Willebrand factor level (a marker of microvessel density) in the same tissue samples. VEGFR2 was expressed by neurons, astrocytes and endothelial cells. VEGFR1 was expressed predominantly neuronally and was significantly reduced in AD (p = 0.02). Western blot analysis on a subset of brains showed reduction in VEGFR1:sVEGFR1 in AD (p = 0.046). The lack of angiogenesis despite cerebral hypoperfusion in AD is not explained by altered expression of VEGFR2 or total VEGFR1; indeed, the downregulation of VEGFR1 may represent a pro-angiogenic response to the hypoperfusion. However, the relative increase in sVEGFR1 would be expected to have an anti-angiogenic effect which may be a factor in AD.

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“…Growth of these endothelial pillars leads to sinusoidal multiplication by successive fusion and partitioning of the existing vascular lumens [80]. A recent study with human endothelial cells shows that chronic hypoxia attenuates VEGF signaling and angiogenic responses by down-regulation of VEGFR-2 [81]. As stated above, most of HCCs originate from fibrosis and cirrhosis, which undergo chronic hypoxia and VEGFR-2 levels were down-regulated in both tumor and in adjacent tissue [78], preferring intussusceptive angiogenesis instead of sprouting angiogenesis.…”

Section: Intussusceptive Angiogenesis In Hccmentioning

confidence: 99%

Angiogenesis: multiple masks in hepatocellular carcinoma and liver regeneration

Chen

Shi

et al. 2010

Hepatol Int

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Hepatocellular carcinoma (HCC) is naturally resistant to radiotherapy and cytotoxic chemotherapy, leaving surgery as the mainstream therapeutic approach. However, the 5-year recurrence rate after curative resection is as high as 61.5%. The background hepatitis B-or C-induced cirrhosis and the presence of micrometastases at the time of surgery have been regarded as two main causes of recurrence. Recently, accumulating evidence suggests that growth factors and cytokines released during the physiological process of post-surgical liver regeneration could induce the activation of dormant micrometastatic lesions. The establishment of neovasculature to support either liver regeneration or HCC growth involves multiple cell types including liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, and circulating endothelial progenitors. The crosstalks among these cells are driven by multiple molecules and signaling pathways, including vascular endothelial growth factors and their receptors, platelet-derived growth factor, the angiopoietin/Tie family, hepatocyte growth factor/c-Met signaling, and others. Anti-angiogenic agent targeting liver cancer vasculature has been reported to be able to generate limited survival benefit of the patients. In this review, discussions are focused on various angiogenic mechanisms of HCC and liver regeneration, as well as the prevailing anti-angiogenic strategies.

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Chronic hypoxia attenuates VEGF signaling and angiogenic responses by downregulation of KDR in human endothelial cells

Cited by 91 publications

References 55 publications

Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney

Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney

VEGFR1 and VEGFR2 in Alzheimer’s Disease

Angiogenesis: multiple masks in hepatocellular carcinoma and liver regeneration

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