Angiotensin receptor MAS1 may have a role in the pathogenesis of endometriosis

High angiotensin receptor MAS1 expression in the endometrium may initiate endometriosis

Key Points

Highlights:

• The renin-angiotensin system (RAS), which is an activation cascade, may have effects on the development of aberrant endometria at ectopic sites. 
• This unique study demonstrates that MAS1 is expressed in the eutopic proliferative endometrium in patients with ovarian endometriotic tissues, suggesting that MAS1 plays a role in the initiation of endometriosis, specifically in the migration of endometrial tissues from the eutopic to the ectopic sites.

Importance:

• The renin-angiotensin system (RAS) is an activation cascade, plays a key role in the regulation of blood pressure, water, and electrolyte homeostasis. Most important roles are in the regulation of tissue remodeling, which contains tissue thickening-sclerosis that is particularly involved in cell proliferation.
• Renin cleaves angiotensinogen into angiotensin and produces angiotensin I, which is further cleaved by angiotensin-converting enzyme 1 (ACE1) to angiotensin II. Angiotensin II is either converted to angiotensin (1–7) by ACE2 which binds to an endogenous ligand for the G protein-coupled receptor Mas (MAS1); or Angiotensin II itself binds to AT1 or AT2.
• The functions of Angiotensin II (vasoconstriction, angiogenesis, and cell growth), are mediated through the AT1 pathway. On the other hand, when angiotensin II binds to AT2; or angiotensin (1–7)-MAS1 pathway is activated, they result in opposing effects on the AT1 pathway.

What's done here:

• In this study, the MAS1 pathway in the endometria of endometriosis patients was investigated using 23 ovarian endometriotic tissues and 15 eutopic endometrial tissues obtained from 29 premenopausal endometriosis patients, and compared to 10 eutopic endometria of patients without endometriosis.
• The hypothesis was that MAS1, opposing the AT1 pathway, would have positive effects on the spread of the eutopic endometria in endometriosis patients.
• The expression patterns of MAS1, AT1, and AT2 in various tissues collected from endometriosis patients were assessed by immunohistochemistry besides RNA extraction, RT, and real-time qPCR were performed.

Key Results:

•  MAS1 Protein is Present in the apical side of the glandular epithelium in ovarian endometriosis.
• mRNA levels of MAS1 also increased significantly in ovarian endometriosis and also were higher in the proliferative endometriosis of the patients compared to those proliferative tissues from endometria of control patients.
• MAS1 was expressed specifically in the proliferative tissues of the endometriosis patients and the expression levels of MAS1 were higher than those of AT1; however, MAS1 and AT2 expression did not cooperate with each other physiologically.

 Limitations:

• As far as the angiotensin (1–7)-MAS1 signaling pathway and its functional analysis tissues were not examined, the direct effect of  MAS1 expression in the eutopic proliferative tissues should be examined in more detailed studies to confirm the role of MAS1. 

Lay Summary

Takahiro Nakajima and colleagues from Nihon University School of Medicine, Tokyo, Japan report their novel findings on Angiotensin receptor MAS1 in the pathogenesis of endometriosis in Gynecologic and Obstetrics Investigation.

The renin-angiotensin system (RAS) is an activation cascade playing a key role in the regulation of blood pressure besides water and electrolyte balance. RAS also plays important roles in regulating tissue remodeling, tissue thickening, and sclerosis; and is particularly involved in cell proliferation, angiogenesis, and apoptosis. Renin cleaves angiotensinogen into angiotensin to produce angiotensin I, which is cleaved by angiotensin-converting enzyme 1 (ACE1) to angiotensin II. Angiotensin II is then converted to angiotensin (1–7) by ACE2, but may also bind to AT1 or AT2, and angiotensin  (1–7) binds to an endogenous ligand for the G protein-coupled receptor Mas (MAS1). This system may play supportive roles in the development of aberrant endometria at ectopic sites.

Nakajima group has previously shown that both AT1 and AT2 receptors are expressed in endometriosis and the ratio of the AT1/AT2 mRNA levels are increased in an endometriosis-specific manner at ectopic sites. Hypothesizing that MAS1, opposing the AT1 pathway, would have positive effects on the spread of the eutopic endometria in the endometriosis patients the expression patterns of MAS1, AT1, and AT2 in various tissues collected from endometriosis patients were investigated.

The immunohistochemical staining protocols with polyclonal antibodies demonstrated that the apical borders of the glandular epithelia in ovarian endometriosis were positive for MAS1. The MAS1 mRNA levels in ovarian endometriosis tissues also increased significantly (p < 0.05) whereas MAS1 mRNA levels were higher in the proliferative endometrium of endometriosis patients when compared to the proliferative tissues from control patient group (p < 0.05). 

MAS1 has an inhibitory effect on the AT1 pathway, which is involved in tissue remodeling processes. The findings indicated that MAS1 expression in the eutopic proliferative tissues was specific to patients with ovarian endometrial cysts. AT2 expression was not correlated.

"Tissue remodeling of the endometrium is thought to play a role in the pathogenesis of endometriosis, and the RAS balance (MAS1/AT1 ratio) in the endometrium might be a critical factor for the initiation of endometriosis" the authors concluded.

Research Source: https://www.ncbi.nlm.nih.gov/pubmed/29982252