TGF-beta in ocular angiogenesis

Abnormal angiogenesis is associated with many blinding eye diseases. Targeting VEGF, a master regulator of blood vessel formation, has shown improved outcomes in ocular vascular disorders. However, many patients do not respond or respond poorly to anti-VEGF therapy, which is not surprising as angiogenesis is regulated by a delicate balance of diverse molecular signals. Combination therapeutics targeting alternative or complementary pathways may circumvent resistance and enhance efficacy of anti-VEGF treatment. TGFβ1, a multifunctional cytokine, plays an important but contradictory role during angiogenesis. We recently identified a novel regulator of TGFβ signaling pathway, namely leucine rich α-2-glycoprotein-1 (LRG1). LRG1 defines the context-dependent effect of TGFβ1 and promotes blood vessel formation by driving the pro-angiogenic TGFβ1/Smad1/5/8 pathway. Unlike VEGF, LRG1 is specifically required for abnormal blood vessel formation in the eye. LRG1 antibody blockade attenuates the ocular angiogenesis either on its own or in combination with an anti-VEGF neutralizing antibody. Together, our study provided compelling evidence that LRG1 is an attractive target for therapeutic intervention in ocular vascular complications.