Involvement of the Endocannabinoid System in the Pathophysiology of Endometriosis

Abstract

Endometriosis (EM) is a prevalent gynecological disorder affecting ~200 million women worldwide. Despite being one of the major causes of hysterectomy, pelvic pain, and infertility, EM remains poorly diagnosed and treated. This is partly due to the lack of knowledge of the molecular mechanisms underlying EM pathogenesis. In this context, the endocannabinoid system (ECS) has emerged as a major player influencing lesion-associated proliferation, vascularization, and pain, however, the precise mechanism of action is yet to be elucidated. This thesis aims to address this knowledge gap by investigating the involvement of the ECS in EM pathogenesis and its potential as a therapeutic target. We specifically explored the complex interplay between the ECS, immune system, and other signaling pathways involved in EM pathophysiology using patient samples, representative cell lines, and mouse models of EM [including homozygous cannabinoid receptor 1 (CNR1/CB1) and cannabinoid receptor 2 (CNR2/CB2) knockout mice]. Deficiency of the ECS has been hypothesized to contribute to EM disease progression and the development of pain symptoms. Indeed, our findings suggest that the ECS plays a crucial role in the inflammatory response and pain modulation in EM, along with a broad role in the female reproductive system. In our studies, we observed differences in anti-inflammatory EC ligands in EM lesions, indicating the involvement of the ECS in inflammation regulation. Specifically, CB2 receptors, found throughout the immune system, are lowly expressed in the lesions of EM patients. Using a broad spectrum CB1 and CB2 agonist (WIN 55), we documented that WIN 55 reduces lesion-associated proliferation and vascularization in a mouse model of EM. Finally, utilizing CNR1 and CNR2 knockout (k/o) and wild-type (WT) mouse models of EM, we reveal the contributions of the ECS and these receptors in disease initiation, progression, and immune modulation. We also demonstrate the impact of decidualization-induced changes on ECS components and the unique disease-specific transcriptional landscape of ECS components in EM. Imaging Mass Cytometry (IMC) analysis highlights the spatial architecture of EM-like lesions and distinct differences between CNR1, CNR2, and WT genotypes in different lesion types. This comprehensive thesis provides an in-depth analysis of ECS involvement in EM pathogenesis and paves the way for the development of novel therapeutic interventions to alleviate the burden of this debilitating condition.