Basic mechanisms of vascularization in endometriosis and their clinical implications

Abstract

BACKGROUND: Vascularization is a major hallmark in the pathogenesis of endometriosis. An increasing number of studies suggests that multiple mechanisms contribute to the vascularization of endometriotic lesions, including angiogenesis, vasculogenesis and inosculation. OBJECTIVE AND RATIONALE: In this review, we provide an overview of the basic mechanisms of vascularization in endometriosis and give special emphasis on their future clinical implications in the diagnosis and therapy of the disease. SEARCH METHODS: Literature searches were performed in PubMed for English articles with the key words ‘endometriosis’, ‘endometriotic lesions’, ‘angiogenesis’, ‘vascularization’, ‘vasculogenesis’, ‘endothelial progenitor cells’ and ‘inosculation’. The searches included both animal and human studies. No restriction was set for the publication date. OUTCOMES: The engraftment of endometriotic lesions is typically associated with angiogenesis, i.e. the formation of new blood vessels from pre-existing ones. This angiogenic process underlies the complex regulation by angiogenic growth factors and hormones, which activate intracellular pathways and associated signaling molecules. In addition, circulating endothelial progenitor cells (EPCs) are mobilized from the bone marrow and recruited into endometriotic lesions, where they are incorporated into the endothelium of newly developing microvessels, referred to as vasculogenesis. Finally, preformed microvessels in shed endometrial fragments inosculate with the surrounding host microvasculature, resulting in a rapid blood supply to the ectopic tissue. These vascularization modes offer different possibilities for the establishment of novel diagnostic and therapeutic approaches. Angiogenic growth factors and EPCs may serve as biomarkers for the diagnosis and classification of endometriosis. Blood vessel formation and mature microvessels in endometriotic lesions may be targeted by means of anti-angiogenic compounds and vascular-disrupting agents. WIDER IMPLICATIONS: The establishment of vascularization-based approaches in the management of endometriosis still represents a major challenge. For diagnostic purposes, reliable angiogenic and vasculogenic biomarker panels exhibiting a high sensitivity and specificity must be identified. For therapeutic purposes, novel compounds selectively targeting the vascularization of endometriotic lesions without inducing severe side effects are required. Recent progress in the field of endometriosis research indicates that these goals may be achieved in the near future.