Angiogenic and Inflammatory Alterations of Endometriotic Lesions in a Transgenic Animal Experimental Model With Loss of Expression of PPAR-Alpha Receptors.

INTRODUCTION: Peroxisome proliferator-activated receptors (PPARs) have been proposed as a medical treatment against endometriosis in preclinical and clinical studies. Their effect seems to be triggered through the suppression of angiogenesis. In the present study, we used a transgenic animal model with a loss of expression of PPAR-alpha receptors to examine their effect on the course of surgically induced endometriotic lesions. METHODS: Ten C57BL/6 mice that served as controls and 10 B6;129S4-PPARatm1Gonz/J t transgenic mice characterized by absolute loss of expression of PPAR-alpha receptors were used for induction of endometriosis with a previously described surgical technique. RESULTS: Five animals (50%) exhibited abundant endometriotic crypts in the control group whereas only one (10%) animal in the transgenic experimental group had a similar pathological image. Neo-vascularization significantly differed among the two groups (p=0.034) favoring the control group as it was extremely limited in half of the PPAR-alpha null animals. The median inflammation score was 2.5 (1-4) in the P B6;129S4-PPARatm1Gonz/J group, whereas it was minimal, 1 (0-2), in the C57BL/6 group. However, these differences were not statistically significant (p=0.101). The fibroblastic activity was also very limited in the PPAR-alpha-deficient model, whereas animals belonging to the control group exhibited an intermediate increase of this index (p=0.022). CONCLUSION: Surgically induced endometriotic implants in animals with loss of expression of PPAR-alpha receptors exhibit significant differences in their pathology compared to lesions induced in control animals. This information suggests that PPAR-alpha receptors have a significant impact on the course of the disease, indicating that they may serve as potential targets for future medical therapies.

A potential role of cyclin-dependent kinase inhibitor 1 (p21/WAF1) in the pathogenesis of endometriosis: Directions for future research.

Endometriosis is a common gynecological disorder that affects approximately 6-10% of the female population impairing the quality of life of patients. Several pathophysiologic pathways have been proposed as potential regulators of its severity; however, to date, the processes that trigger the onset and that influence the severity of the disease are not fully understood; hence, leading to disease recurrence in approximately 10-67% of cases. Cyclin-dependent kinase inhibitor 1 (p21/WAF1) is a protein that is a major target of p53 and is related to cell cycle arrest (it regulates transition from the G1 to the S phase) when DNA damage is detected. Its activity has been also linked to the angiogenic potential of tumors as it promotes the expression of various kinases that are responsible for endothelial development and function. Although several articles have underlined the importance of this protein in cancer cell development and tumor growth, there are no relevant data in the field of endometriosis. Indirect evidence suggests, however, that it may be involved in the pathogenesis of endometriosis as it inhibits the activity of various kinases which have been correlated with the course and severity of the disease. The present article investigates the background theory that implies the potential role of cyclin-dependent kinase inhibitor 1 (p21/WAF1) in the pathogenesis of endometriosis. Implications for future research are also provided given that indirect evidence seem to associate downregulation of p21 with decreased growth and invasiveness of human endometrial stromal cells.