Angiogenesis, the growth of new blood vessels, is essential to normal development and to pathological states such as cancer and rheumatoid arthritis (RA). Developing tissues and tumors cannot survive without the nutrients that blood vessels supply. The process of angiogenesis is influenced by growth factors and integrins. Prior research has indicated that the integrins avb3 and avb5 are important in angiogenesis. These studies found that inhibition of avb3 or avb5 suppressed the formation of new blood vessels as well as tumor growth. In this study, Reynolds et al (Nature Medicine 8:27-34, 2002) examined angiogenesis and tumorigenesis in mice lacking b3 or both 3 and b5 integrins.
Tumor angiogenesis in b3-deficient mice was examined by injecting b3-null and wild-type mice with murine tumor cells.
Tumors grew in both mouse lines, with tumor size actually enhanced in the b3-deficient mice. Enhanced tumorigenesis was also found in the mice deficient for both b3 and b5. Additionally, tumors from the b3, b5-deficient mice exhibited a higher density of blood vessels when compared to tumors from the control group. In b3-null cells, vascular endothelial growth factor receptor-2 (VEGFR-2) expression was increased. VEGF is a growth factor that stimulates angiogenesis.
These data indicate that b3 and b5 integrins are not essential to the development of new blood vessels and demonstrate the need for further research into the mechanisms of integrin inhibitors in anti-angiogenic therapies.
To date, avb3 and avb5 have been thought to be essential for both development and pathological angiogenesis. Angiogenesis is a prominent feature of the synovium in RA and inhibition of avb3/5 are currently in development and/or clinical trial for the treatment of RA. The results demonstrated in this study of b3-null and b3/b5 -null mice are unexpected and totally opposite to what was hypothesized. The authors suggest that perhaps the role of avb3 and avb5 is not the promotion of angiogenesis but rather its negative regulation. They also discuss a number of other possible mechanisms.
At any rate, the results of this study call for a more thorough understanding of the role of integrins in angiogenesis. It would be interesting to evaluate the effect of av3/av5 knockout on the induction of arthritis in susceptible mice. It is remotely possible that b3-null and/or b5-null mice could exhibit enhanced synovial growth and inflammation in response to arthritogenic stimuli, compared to wildtype controls.