Angiogenesis promoted by vascular endothelial growth factor: Regulation through α₁β₁and α₂β₁integrins

Abstract

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is a cytokine of central importance for the angiogenesis associated with cancers and other pathologies. Because angiogenesis often involves endothelial cell (EC) migration and proliferation within a collagen-rich extracellular matrix, we investigated the possibility that VEGF promotes neovascularization through regulation of collagen receptor expression. VEGF induced a 5-to 7-fold increase in dermal microvascular EC surface protein expression of two collagen receptors-the ␣ 1 ␤ 1 and ␣ 2 ␤ 1 integrins-through induction of mRNAs encoding the ␣ 1 and ␣ 2 subunits. In contrast, VEGF did not induce increased expression of the ␣ 3 ␤ 1 integrin, which also has been implicated in collagen binding. Integrin ␣ 1 -blocking and ␣ 2 -blocking antibodies (Ab) each partially inhibited attachment of microvascular EC to collagen I, and ␣ 1 -blocking Ab also inhibited attachment to collagen IV and laminin-1. Induction of ␣ 1 ␤ 1 and ␣ 2 ␤ 1 expression by VEGF promoted cell spreading on collagen I gels which was abolished by a combination of ␣ 1 -blocking and ␣ 2 -blocking Abs. In vivo, a combination of ␣ 1 -blocking and ␣ 2 -blocking Abs markedly inhibited VEGF-driven angiogenesis; average cross-sectional area of individual new blood vessels was reduced 90% and average total new vascular area was reduced 82% without detectable effects on the pre-existing vasculature. These data indicate that induction of ␣ 1 ␤ 1 and ␣ 2 ␤ 1 expression by EC is an important mechanism by which VEGF promotes angiogenesis and that ␣ 1 ␤ 1 and ␣ 2 ␤ 1 antagonists may prove effective in inhibiting VEGF-driven angiogenesis in cancers and other important pathologies.

Anti-Very Late Antigen-1 Monoclonal Antibody Modulates the Development of Secondary Lesion and T-Cell Response in Experimental Arthritis

“…Of course we cannot exclude that the situation in the lymph nodes may reflect a more complex effect at the systemic level, not only HA31/8 (0.1-0.3 mg/kg iv) Ianaro et al on lymphocytes, due to the wide distribution of this integrin. Indeed, elevated expression of vascular endothelial growth factor has been found in RA (Fava et al, 1994), and it has been shown that angiogenesis of human endothelial cells, promoted by vascular endothelial growth factor in vitro, is suppressed by antibody directed against ␣ 1 ␤ 1 ␣ 2 ␤ 1 integrins (Senger et al, 1997). The importance of the role of VLA-1 in this RA model is further stressed by the finding that HA31/8 causes a pronounced reduction of T cells expressing the IL-2 receptor as well as a reduction of the number of receptors expressed on the cells (MIF%).…”

Integrins: roles in cancer development and as treatment targets

“…Integrin avb5 promotes VEGF-, but not bFGF-, mediated angiogenesis (Friedlander et al, 1995). Integrin receptors for laminin and collagen also play roles in regulating blood vessel formation as antagonists of a2b1 and a1b1 suppressed VEGFmediated angiogenesis (Senger et al, 1997). Thus, integrins play key roles in regulating tumour angiogenesis, and integrin antagonists hold promise as future therapeutics for cancer.…”

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

“…The acquisition of a migratory/ metastatic phenotype is often associated with changes to the expression and activation states of integrins that affect cell attachment to ECM, regulate the balance between cell adhesion and motility and enable cell survival under conditions of detachment, a critical requirement for metastasis (reviewed in Felding-Habermann, 2003). The expression of a2b1 integrin, a type IV collagen receptor (Vandenberg et al, 1991), is regulated by growth factors and plays a role in angiogenesis (Senger et al, 1997), altered cell adhesion, survival, growth and metastasis of malignant cells (Krensel and Lichtner, 1999).…”