Vascular endothelial growth factor is essential for corpus luteum angiogenesis

Ferrara, Napoleone; Chen, Helen; Davis-Smyth, Terri; Gerber, Hans‐Peter; T, N'Guyen; Peers, David H.; Chisholm, Vanessa; Hillan, Kenneth J.; Schwall, Ralph

doi:10.1038/nm0398-336

Cited by 565 publications

(394 citation statements)

References 17 publications

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“…On the other hand, the results of a phase I clinical trial with VEGF inhibitors showed that these agents were well tolerated, 34 indicating a marginal role for VEGF signalling in normal organs under physiological conditions except the ovary during the menstrual cycle. 35 Another problem for the clinical use of a type II CRAd is that the relevant promoter activity in each tumor should be evaluated before treatment. From previous reports as well as our results, it is clear that tumors with low promoter activity are resistant to type II CRAds containing that promoter.…”

Section: Discussionmentioning

confidence: 99%

Vascular endothelial growth factor promoter-based conditionally replicative adenoviruses for pan-carcinoma application

Takayama

Adachi

et al. 2006

Cancer Gene Ther

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Treatment of advanced lung cancer is one of the major challenges in current medicine because of the high morbidity and mortality of the disease. Advanced stage lung cancer is refractory to conventional therapies and has an extremely poor prognosis. Thus, new therapeutic approaches are needed. Lung tumor formation depends on angiogenesis in which the vascular endothelial growth factor (VEGF) produced by cancer cells plays a pivotal role. Neutralizing VEGF with a soluble VEGF receptor suppresses tumor growth; however, the anticancer effect with this therapy is weakened after the intratumoral vascular network is completed. In this study, we turned the expression of VEGF by tumors to therapeutic advantage using a conditionally replication-competent adenovirus (CRAd) in which the expression of E1 is controlled by the human VEGF promoter. This virus achieved good levels of viral replication in lung cancer cells and induced a substantial anticancer effect in vitro and in vivo. As a further enhancement, the cancer cell killing effect was improved with tropism modification of the virus to express the knob domain of Ad3, which improved infectivity for cancer cells. These VEGF promoter-based CRAds also showed a significant cell killing effect for various types of cancer lines other than lung cancer. Conversely, the VEGF promoter has low activity in normal tissues, and the CRAd caused no damage to normal bronchial epithelial cells. Since tumor-associated angiogenesis via VEGF signalling is common in many types of cancers, these CRAds may be applicable to a wide range of tumors. We concluded that VEGF promoter-based CRAds have the potential to be an effective strategy for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Vascular endothelial growth factor promoter-based conditionally replicative adenoviruses for pan-carcinoma application

Takayama

Adachi

et al. 2006

Cancer Gene Ther

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“…Given the synchronized nature of neovascularization in this cyclical process, it is assumed that angiogenic growth factor expression is induced by steroid hormones and regulates blood vessel formation in reproductive organogenesis. [113][114][115][116] Indeed, physiological changes in the reproductive tract during the normal menstrual cycle 28 as well as physiological and pathological symptoms, including telangiectasia of pregnancy 117 and telangiectasia in postsclerotherapy patients receiving gonadal hormones, 118 are all associated with elevated levels of serum estradiol.…”

Section: Hormone-regulated Neovascularizationmentioning

confidence: 99%

Estrogen and Angiogenesis

Losordo

Isner

2001

ATVB

301

194

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Abstract-Multiple lines of evidence suggest that estrogen directly modulates angiogenesis via effects on endothelial cells.Under physiological conditions, angiogenesis is routinely observed in the uterus in association with fluctuations in the levels of circulating estradiol and other sex steroids. In pathological circumstances, such as breast cancer, a clear association between estrogen, estrogen receptor expression by endothelial cells, angiogenic activity, and/or tumor invasiveness has been made. Studies performed in our laboratory have revealed that estradiol accelerates functional endothelial recovery after arterial injury. Despite these consistent observations, the mechanisms by which estrogen regulates angiogenesis under physiological and pathological circumstances have not been defined. Key Words: estrogen Ⅲ angiogenesis Ⅲ vasculogenesis Ⅲ endothelium Ⅲ endothelial progenitor cells I n adult organisms, angiogenesis is virtually absent under normal conditions, except in the female reproductive tract. This observation suggests the potential for sex steroids to influence neovascularization. Several other associations, including the predilection of certain diseases (such as Takayasu's arteritis and lupus, both of which involve endothelial cell proliferation) for premenopausal females, also imply the potential role of estrogen in angiogenesis. 1,2 The role of estradiol in uterine angiogenesis, mediated by at least 1 of the estrogen receptors, has been further suggested by findings in the estrogen receptor-␣ knockout mouse, in which angiogenesis is impaired, 3 and by the demonstration that estrogen receptor antagonists can inhibit angiogenesis. 4 The positive correlation between estrogen receptor expression, angiogenic activity, and breast tumor invasiveness also supports the angiogenic effect of estrogen mediated by the estrogen receptor(s). [5][6][7][8] Finally, some reports suggest that the antitumor effect of tamoxifen may in fact relate to an antiangiogenic action of this estrogen receptor agonist/antagonist. 9 Several additional lines of experimental evidence suggest that estrogen and other sex steroids play important roles in physiological and pathological angiogenesis. One of the first observations suggesting a hormonal influence on angiogenesis was an inhibitory effect on tumor vascularization by medroxyprogesterone. 10 Subsequent studies have indicated that the mechanism of this inhibition may relate to the regulation of thrombospondin-1, an angiogenesis inhibitor, by this hormone. 11 Angiogenesis has been noted to be a prognostic marker in breast cancer, 12 and inhibition of angiogenesis in these tumors has been effected by antiestrogens. 4 In addition, the estrogen metabolite 2-methoxyestradiol has been shown to be a potent antiangiogenic agent 13 mediated by actions on cytoskeletal structure 14 and by increasing endothelial cell apoptosis. 15,16 Vascular Endothelial Cell Proliferation and Migration Are Enhanced by EstradiolEstradiol induces endothelial proliferation and migration 17 mediated by t...

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“…Treatment with either AZD2932 (VEGFR and PDGFR inhibitor; or a combination of AZD2171 (Cediranib; VEGFR inhibitor; Wedge et al 2005) and AZ12585313 (PDGFRa and b inhibitor), which were dosed to achieve approximately 1:1 inhibition of the PDGFR and VEFGR receptors, resulted in avascular necrosis and a reduction in the number and size of corpora lutea in the ovary-essentially identical changes to those induced by VEGFR inhibition alone (Ferrara et al 1998) and similar to those induced by Sunitinib, which inhibits both VEGFR and PDGFR receptors (as well as c-Kit, FLT3, and RET receptors; Patyna et al 2008). These experiments therefore confirmed that during ovarian angiogenesis, VEGFR inhibition was dominant to PDGFR inhibition, consistent with the sequential cascade of endothelial vascularization followed by pericyte stabilization during angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

PDGFR Inhibition Results in Pericyte Depletion and Hemorrhage into the Corpus Luteum of the Rat Ovary

et al. 2015

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The growth plate, ovary, adrenal gland, and rodent incisor tooth are sentinel organs for antiangiogenic effects since they respond reliably, quantitatively, and sensitively to inhibition of the vascular endothelial growth factor receptor (VEGFR). Here we report that treatment of rats with platelet-derived growth factor receptor beta (PDGFRb) inhibitors that target pericytes results in severe ovarian hemorrhage with degeneration and eventual rupture of the corpus luteum. Evaluation of the growth plate, adrenal gland, and incisor tooth that are typical target organs for antiangiogenic treatment in the rodent revealed no abnormalities. Histologically, the changes in the ovary were characterized by sinusoidal dilatation, increased vessel fragility, and hemorrhage into the corpus luteum. Immunocytochemical staining of vessels with alpha smooth muscle actin and CD31 that recognize pericytes and vascular endothelium, respectively, demonstrated that this effect was due to selective pericyte deficiency within corpora lutea. Further experiments in which rats were treated concurrently with both PDGFRb and VEGFR inhibitors ablated the hemorrhagic response, resulting instead in corpus luteum necrosis. These changes are consistent with the notion that selective pericyte loss in the primitive capillary network resulted in increased vessel fragility and hemorrhage, whereas concomitant VEGFR inhibition resulted in vessel regression and reduced vascular perfusion that restricted development of the hemorrhagic vessels. These results also highlight the utility of the rodent ovary to respond differentially to VEGFR and PDGFR inhibitors, which may provide useful information during routine safety assessment for determining target organ toxicity.

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Vascular endothelial growth factor is essential for corpus luteum angiogenesis

Cited by 565 publications

References 17 publications

Vascular endothelial growth factor promoter-based conditionally replicative adenoviruses for pan-carcinoma application

Vascular endothelial growth factor promoter-based conditionally replicative adenoviruses for pan-carcinoma application

Estrogen and Angiogenesis

PDGFR Inhibition Results in Pericyte Depletion and Hemorrhage into the Corpus Luteum of the Rat Ovary

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