VEGF function in vascular pathogenesis.

Yin-Shan Ng; Dominik Krilleke; David T Shima

doi:10.1016/j.yexcr.2005.11.008

Home/Archive/PubMed

PubMed · 16330026

VEGF function in vascular pathogenesis.

Yin-Shan Ng·Dominik Krilleke·David T Shima

View original source ↗Export metadata ↓

Abstract

Vascular endothelial growth factor (VEGF) has proven to be the most critical angiogenic factor identified to date; its discovery has transformed the field of angiogenesis research. After two decades of intense studies by numerous laboratories, the complex biology of VEGF is slowly being elucidated. VEGF is a collection of several different isoforms with overlapping but also unique functions. Furthermore, there are at least four different VEGF receptors, adding to the complexity of the VEGF/receptor system. VEGF exerts its effects on endothelial cells, inflammatory cells and neuronal cells, and its expression may contribute to the pathologies of diseases ranging from retinopathies to cancer. This review focuses on the biochemistry and cell biology of VEGF, with particular emphasis on the different isoforms and receptors, thereby illustrating the multifunctional nature of this growth factor. Lastly, critical considerations based on the complex biology of VEGF for developing specific and more targeted anti-VEGF therapeutic agents will be discussed.

Explore related subjects

Angiogenesis Inhibitors Animals Endothelium, Vascular Humans Neovascularization, Pathologic Protein Isoforms Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factor Receptor-2 Journal Article Review

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Yin-Shan Ng, Dominik Krilleke, David T Shima. 2005-12-05. VEGF function in vascular pathogenesis.. https://doi.org/10.1016/j.yexcr.2005.11.008

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2007

Molecular mechanism of emodin action: transition from laxative ingredient to an antitumor agent.

Anthraquinones represent a large family of compounds having diverse biological properties. Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is a naturally occurring anthraquinone present in the roots and barks of numerous plants, molds, and lichens, and an active ingredient of various Chinese herbs. Earlier studies have documented mutagenic/genotoxic effects of emodin, mainly in bacterial system. Emodin, first assigned to be a specific inhibitor of the protein tyrosine kinase p65lck, has now a number of cellular targets interacting with it. Its inhibitory effect on mammalian cell cycle modulation in specific oncogene overexpressed cells formed the basis of using this compound as an anticancer agent. Identification of apoptosis as a mechanism of elimination of cells treated with cytotoxic agents initiated new studies deciphering the mechanism of apoptosis induced by emodin. At present, its role in combination chemotherapy with standard drugs to reduce toxicity and to enhance efficacy is pursued vigorously. Its additional inhibitory effects on angiogenic and metastasis regulatory processes make emodin a sensible candidate as a specific blocker of tumor-associated events. Additionally, because of its quinone structure, emodin may interfere with electron transport process and in altering cellular redox status, which may account for its cytotoxic properties in different systems. However, there is no documentation available which reviews the biological activities of emodin, in particular, its growth inhibitory effects. This review is an attempt to analyze the biological properties of emodin, a molecule offering a broad therapeutic window, which in future may become a member of anticancer armamentarium.

Angiogenesis Inhibitors↗

PubMed2007

Targeting VEGF-A to treat cancer and age-related macular degeneration.

Inhibiting angiogenesis is a promising strategy to treat cancer and several other disorders, including intraocular neovascular syndromes. The identification of vascular endothelial growth factor (VEGF)-A as a major regulator of normal and pathological angiogenesis has enabled significant progress toward effective treatments for such disorders. Several VEGF inhibitors have been recently approved by the U.S. Food and Drug Administration for the treatment of cancer and the neovascular form of age-related macular degeneration. This review summarizes the basic biology of VEGF-A and illustrates the clinical progress in targeting this molecule.

Angiogenesis Inhibitors↗

PubMed2006

Identification of ABR-215050 as lead second generation quinoline-3-carboxamide anti-angiogenic agent for the treatment of prostate cancer.

BACKGROUND: Linomide, Figure 1, produces robust and consistent in vivo growth inhibition of prostate cancer models via its anti-angiogenic activity and inhibition of autoimmune encephalomyelitis models of multiple sclerosis (MS). MS clinical trials were discontinued because of unacceptable toxicity, due to dose-dependent induction of proinflammation. METHODS: Therefore, linomide analogs were initially screened to determine their in vivo potency to inhibit growth of the Dunning R-3327 AT-1 rat prostate cancer model in rats and their potency to inhibit angiogenesis in a Matrigel assay in mice. RESULTS: Based upon its superior potency (i.e., 30- to 60-fold more potent than linomide) in these assays and its lack of a proinflammation in the Beagle-dog, ABR-215050 (tasquinimod), Figure 1, was characterized for dose-response ability to inhibit the growth of a series of four additional human and rodent prostate cancer models in mice. Pharmacokinetic analysis following oral dosing documented that blood and tumor tissue levels of ABR-215050 as low as 0.5-1 microM are therapeutically effective. This efficacy is correlated with inhibition of angiogenesis in a variety of assays (endothelial capillary tube formation, aortic ring assay, chorioallantoic membrane assay, real-time tumor blood flow and PO(2) measurements, tumor blood vessel density, and tumor hypoxic and apoptotic fractions). CONCLUSIONS: Based upon its robust and consistent anti-angiogenic activity and thus tumor growth, ABR-215050 has entered clinical trials for the treatment of prostate cancer.

Angiogenesis Inhibitors↗