Characterization of elevated levels of endometrial renin–angiotensin system components suggest a role in endometrial repair

Introduction Each month, the endometrium is shed, regenerated, and transformed in response to changing hormone levels. These processes occur in a tightly regulated manner, and irregularities are linked with reproductive health conditions such as endometriosis and infertility. The renin–angiotensin system is known to be under hormonal control and to drive proliferation and differentiation in tissues, but its expression across the endometrial cycle is not well characterized. Therefore, this study aimed to describe the spatial–temporal localization and gene expression of key initiators of renin–angiotensin system signaling, prorenin, the prorenin receptor, and angiotensinogen, across the endometrial cycle. Methods Endometrial tissue was collected from participants within the proliferative phase, mid-secretory phase, and late-secretory phase of their endometrial cycle (n=10/phase). Prorenin ( REN ), the prorenin receptor ( ATP6AP2 ), and angiotensinogen ( AGT ) mRNA levels were quantified by qPCR. The spatial localization of proteins was determined using immunohistochemistry and immunolabeling quantified using HALO image analysis software. Results Both prorenin ( REN ) mRNA expression and protein immunolabeling intensity were detected at low levels within endometrial tissue, where cell type significantly affected immunolabeling intensity. The mRNA expression of ATP6AP2 was higher in the proliferative phase compared to the late-secretory phase, with strong prorenin receptor protein immunolabeling across the endometrial cycle, most intensely in the glandular epithelium. AGT mRNA expression was higher in the proliferative phase compared to the late-secretory phase endometrium. Mixed effects analysis demonstrated that the angiotensinogen protein labeling intensity was influenced by endometrial cell type but not cycle phase and was highest in the endometrial stroma. There was, however, an interaction between cell type and phase whereby angiotensinogen immunolabeling in the stroma tended to be stronger in the mid-secretory phase compared with the late-secretory phase. Conclusion AGT and ATP6AP2 mRNA levels are higher in the proliferative phase compared to the late-secretory phase of the endometrial cycle. Angiotensinogen immunolabeling is highest in the stroma regardless of cycle phase and tends to be lower in the stroma of the late-secretory phase compared to the mid-secretory phase. These findings suggest that the renin–angiotensin system may play a regulatory role in driving stromal regeneration and proliferation in the proliferative and mid-secretory phase of the endometrial cycle.