Relapse of pathological angiogenesis: functional role of the basement membrane and potential treatment strategies

Blinding eye diseases such as corneal neovascularization, proliferative diabetic retinopathy, and age-related macular degeneration are driven by pathological angiogenesis. In cancer, angiogenesis is key for tumor growth and metastasis. Current antiangiogenic treatments applied clinically interfere with the VEGF signaling pathway-the main angiogenic pathway-to inhibit angiogenesis. These treatments are, however, only partially effective in regressing new pathologic vessels, and the disease relapses following cessation of treatment. Moreover, the relapse of pathological angiogenesis can be rapid, aggressive and more difficult to treat than angiogenesis in the initial phase. The manner in which relapse occurs is poorly understood; however, recent studies have begun to shed light on the mechanisms underlying the revascularization process. Hypotheses have been generated to explain the rapid angiogenic relapse and increased resistance of relapsed disease to treatment. In this context, the present review summarizes knowledge of the various mechanisms of disease relapse gained from different experimental models of pathological angiogenesis. In addition, the basement membrane-a remnant of regressed vessels-is examined in detail to discuss its potential role in disease relapse. Finally, approaches for gaining a better understanding of the relapse process are discussed, including prospects for the management of relapse in the context of disease. Blood vessel formation: understanding relapse after inhibitory treatment Studying the sites of previous blood vessel occupation may explain how pathological vessel growth recurs after inhibitory treatment. Angiogenesis, the growth of new blood vessels, drives progression of cancerous tumors and blinding eye diseases. Existing treatments inhibiting critical growth factors are effective in the short term, but are often followed by aggressive relapse. Mukwaya et al., from Linkoping University in Sweden review the role of empty basement membrane sleeves (EBMS), the remnants of regressed blood vessels. Basement membrane supports endothelial cells, and EBMS could act as a scaffold for endothelial cells to rapidly rebuild blood vessels after anti-angiogenic treatment. Alternatively, EBMS may represent irreversibly abandoned conduits permanently isolated from the circulation, putatively through the deposition of excess collagen. Future work should carefully examine the role of basement membrane in the relapse of pathologic vessel growth.

Automated summary

This article discusses the mechanisms of relapse in pathological angiogenesis and the potential role of the basement membrane in disease relapse, emphasizing the importance of research and management strategies for relapse.