Roles for VEGF in the adult
Introduction
Vascular endothelial growth factor (VEGF, VEGF-A or VPF) was first described as a tumor-derived factor with potent ability to induce endothelial cell permeability (Senger et al., 1983), proliferation and angiogenesis (Ferrara and Henzel, 1989, Connolly et al., 1989). Since its initial discovery, VEGF's action on endothelial cells (ECs) has been expanded to include migration and invasion into the basement membrane, proliferation, survival and the formation of fenestrations, which has largely been elucidated using in vitro and in vivo tumor studies. VEGF is biologically active as a homodimer of approximately 40 kDa, belonging to a family of secreted glycoproteins, including VEGF-B, -C, -D and placenta growth factor (PlGF). During development, VEGF expression initiates prior to gastrulation (Miquerol et al., 1999), and is important in both vasculogenesis, the process by which blood vessels develop de novo from endothelial cell precursors, and angiogenesis, in which blood vessels sprout from existing blood vessels (Ferrara, 2004, Coultas et al., 2005). Deletion of either a single or both alleles of the VEGF gene in mice results in embryonic lethality by E9.5 and E10.5 with severe vascular abnormalities (Carmeliet et al., 1996, Ferrara et al., 1996). Furthermore, overexpression of VEGF also results in embryonic lethality (Miquerol et al., 2000). These observations underscore the importance of proper regulation of VEGF expression for normal development. VEGF signaling is mediated via two receptors: VEGFR1/Flt1 and VEGFR2/Flk1; homozygous mutation of either of these receptors results in embryonic lethality (Fong et al., 1995, Shalaby et al., 1995, de Vries et al., 1992). In addition, two co-receptors for VEGF, neuropilin-1 and -2 (Nrp-1 and Nrp-2) (Gluzman-Poltorak et al., 2000, Soker et al., 1998), are also required embryonically (Kawasaki et al., 1999, Takashima et al., 2002). The relative contributions of the various VEGF receptors to VEGF signaling in different endothelial cell beds are not well studied.
While extensive research has shown that VEGF is crucial for developmental, physiologic and pathologic angiogenesis, whether it is required in the adult is unclear. Early studies of genetic VEGF targeting (Ferrara et al., 1996, Gerber et al., 1999) and neutralization studies in tumorigenic mice (Kuo et al., 2001) suggested that VEGF is not required in the adult as these adult mice showed no obvious phenotype, making VEGF an attractive target in many diseases. As a result, a wealth of pharmacologic agents have been designed to target either VEGF or its receptors. Though beneficial effects have been observed, the presence of consistent significant side effects suggests that VEGF is important in the maintenance of quiescent vasculature and non-vascular tissues. This review discusses the expression of VEGF and its receptors in adult tissue, VEGF association with fenestrated vasculature, VEGF effects on non-vascular cells, conditions and factors that may affect VEGF action, and implications for manipulating VEGF in disease treatment.
Section snippets
VEGF expression in the adult
VEGF is robustly expressed embryologically, and is critical for proper blood vessel formation, but its expression is also important in the adult in mediating physiologic angiogenesis during the female reproductive cycle in the uterus, ovary and breast (Otani et al., 1999, Fraser, 2006), in wound healing (Eming and Krieg, 2006, Detmar et al., 1998), in bone repair (Street et al., 2002) and in skeletal muscle in response to exercise (Mac Gabhann et al., 2007). VEGF is also upregulated and
Side effects from clinical systemic VEGF neutralization
All cells require oxygen, and due to the limits of oxygen diffusion, cells more than 100 μm away from blood vessels become oxygen deprived. For this reason, solid tumors are restricted to a size of 1 mm3 without neovascularization. The discovery of a tumor-secreted, angiogenic factor (Folkman et al., 1971), which was later identified as VEGF (Connolly et al., 1989), and was hypoxia-inducible (Shweiki et al., 1992), led to the concept that neutralization of VEGF could block tumor-induced blood
Vascular stability
While therapeutic VEGF neutralization and preeclampsia have revealed potential roles for VEGF in the adult, experimental studies in rodents have begun to unravel the nature of VEGF function in quiescent tissues. Inhibition of VEGF or its receptors has been shown to lead to alteration of the microvasculature as well as to vessel regression in a number of tissues. In the kidney neutralizing VEGF resulted in glomerular endotheliosis and proteinuria (Figs. 3C, F) (Maynard et al., 2003, Eremina et
Biochemical, molecular and cellular factors affecting VEGF signaling in vivo
Although VEGF is expressed in the adult, and is a potent angiogenic factor, it does not result in widespread angiogenesis in resting tissue. The discovery of multiple pro-angiogenic and endogenous anti-angiogenic factors (Folkman, 2004) with overlapping expression patterns indicates that angiogenesis is dependent on a balance between pro- and anti-angiogenic factors. In addition to countering the action of local angiogenic factors in quiescent tissue, endogenous factors maintain avascularity,
Implications for therapeutic manipulation of VEGF
The role of VEGF in development and pathology is well known and emerging evidence points to a role for VEGF in the maintenance of quiescent tissues. Knowledge of adverse effects associated with anti-VEGF therapy, observations from preeclampsia, and experimental blockade of VEGF in animal models have exposed tissues and vascular beds sensitive to VEGF neutralization and revealed potential limitations of current anti-VEGF therapy. One of the most frequently observed side effects of VEGF
Acknowledgments
We thank Dr. Janice Nagy, Dr. Robyn Loureiro and Ms. Christine Bagley for helpful discussions and critical review of the manuscript. This work was supported by NIH EY05318, EY15435 and CA45548 (P.A.D), and NIGMS minority pre-doctoral fellowship, NIH-F31-GM65079 (A.S.R.M).
References (188)
- et al.
Cell type specific expression of vascular endothelial growth factor and angiopoietin-1 and -2 suggests an important role of astrocytes in cerebellar vascularization
Mech. Dev.
(2001) - et al.
Heparin regulates vascular endothelial growth factor165-dependent mitogenic activity, tube formation, and its receptor phosphorylation of human endothelial cells. Comparison of the effects of heparin and modified heparins
J. Biol. Chem.
(2005) - et al.
Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1
Blood
(1996) - et al.
Autocrine–paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor
Blood
(2003) - et al.
The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis
J. Biol. Chem.
(1996) - et al.
Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival
Dev. Biol.
(2003) - et al.
Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial
Lancet
(2006) - et al.
Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice
J. Invest. Dermatol.
(1998) - et al.
Vascular endothelial growth factor-165 overexpression stimulates angiogenesis and induces cyst formation and macrophage infiltration in human ovarian cancer xenografts
Am. J. Pathol.
(2002) - et al.
Molecular mechanisms of VEGF-A action during tissue repair
J. Invest. Dermatol.
(2006)
Immunocytochemical localization of vascular endothelial growth factor in neurons and glial cells of human retina
Brain Res.
Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells
Biochem. Biophys. Res. Commun.
Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner
J. Biol. Chem.
Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia
J. Biol. Chem.
Hepatocyte growth factor/scatter factor (HGF/SF) induces vascular permeability factor (VPF/VEGF) expression by cultured keratinocytes
J. Invest. Dermatol.
Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165 [corrected]
J. Biol. Chem.
VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells
Cell
Pathophysiology of capillary haemangioma growth after birth
Med. Hypotheses
Bowel perforation from bevacizumab for the treatment of metastatic colon cancer: incidence, etiology, and management
Curr. Surg.
The adaptor protein shb binds to tyrosine 1175 in vascular endothelial growth factor (VEGF) receptor-2 and regulates VEGF-dependent cellular migration
J. Biol. Chem.
Pathogenesis of lesions in late age-related macular disease
Am. J. Ophthalmol.
Release and complex formation of soluble VEGFR-1 from endothelial cells and biological fluids
Lab. Invest.
Bevacizumab in the treatment of metastatic colorectal cancer: safety profile and management of adverse events
Semin. Oncol.
Long-term treatment with bevacizumab for patients with metastatic colorectal cancer: case report
Clin. Colorectal Cancer
Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts
Am. J. Pathol.
Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR
Biochem. Biophys. Res. Commun.
Role of VEGF-A in vascularization of pancreatic islets
Curr. Biol.
Generation of a novel proteolysis resistant vascular endothelial growth factor165 variant by a site-directed mutation at the plasmin sensitive cleavage site
FEBS Lett.
Reversible posterior leukoencephalopathy syndrome after bevacizumab/FOLFIRI regimen for metastatic colon cancer
Arch. Neurol.
Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity
Nat. Med.
Corneal avascularity is due to soluble VEGF receptor-1
Nature
Soluble vascular endothelial growth factor receptor-1 contributes to the corneal anti-angiogenic barrier
Br. J. Ophthalmol.
VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model
Nature
Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling
Am. J. Physiol.: Heart Circ. Physiol.
Angiopoietin-1 decreases plasma leakage by reducing number and size of endothelial gaps in venules
Am. J. Physiol.: Heart Circ. Physiol.
Regulation of microvascular permeability by vascular endothelial growth factors
J. Anat.
Lower-extremity edema associated with gene transfer of naked DNA encoding vascular endothelial growth factor
Ann. Intern. Med.
Differential effects of vascular endothelial growth factor receptor-2 inhibitor ZD6474 on circulating endothelial progenitors and mature circulating endothelial cells: implications for use as a surrogate marker of antiangiogenic activity
Clin. Cancer Res.
Angiogenesis in human normal and pathologic adrenal cortex
J. Clin. Endocrinol. Metab.
Vascular endothelial growth factor-A promotes peritumoral lymphangiogenesis and lymphatic metastasis
Cancer Res.
Increased plasma vascular endothelial growth factor (VEGF) as a surrogate marker for optimal therapeutic dosing of VEGF receptor-2 monoclonal antibodies
Cancer Res.
Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only
Circulation
Ranibizumab versus verteporfin for neovascular age-related macular degeneration
N. Engl. J. Med.
Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF)
J. Cell Mol. Med.
Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF
Proc. Natl. Acad Sci. U. S. A.
Comparative evaluation of FGF-2-, VEGF-A-, and VEGF-C-induced angiogenesis, lymphangiogenesis, vascular fenestrations, and permeability
Circ. Res.
Angiogenesis in cancer and other diseases
Nature
Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele
Nature
Urinary VEGF and MMP levels as predictive markers of 1-year progression-free survival in cancer patients treated with radiation therapy: a longitudinal study of protein kinetics throughout tumor progression and therapy
J. Clin. Oncol.
Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice
Nat. Med.
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