title: Combined blockade of angiotensin II type 1 receptor and activation of peroxisome proliferator-activated receptor-γ by telmisartan effectively inhibits vascularization and growth of murine endometriosis-like lesions.
abstract: OBJECTIVE
  Is telmisartan effective in the treatment of endometriosis?
  
  
  CONCLUSIONS
  Combined blockade of angiotensin II type 1 receptor (AT1R) and activation of peroxisome proliferator-activated receptor (PPAR)-γ by telmisartan inhibits vascularization and growth of murine endometriosis-like lesions.
  
  
  BACKGROUND
  AT1R and PPAR-γ are involved in the regulation of inflammation, proliferation and angiogenesis. These processes are also crucial for the pathogenesis of endometriosis and both receptors are expressed in endometrial tissue. Telmisartan is a partial agonist of PPAR-γ, which additionally blocks AT1R.
  
  
  METHODS
  This was a randomized study in the mouse dorsal skinfold chamber and peritoneal model of endometriosis. Endometriosis-like lesions were induced in dorsal skinfold chambers of 21 female C57BL/6 mice, and in the peritoneal cavity of 15 additional animals, which were daily treated with an i.p. injection of pioglitazone (10 mg/kg, n = 12), telmisartan (10 mg/kg, n = 12) or vehicle (5% dimethyl sulfoxide (DMSO), n = 12) throughout an observation period of 14 and 28 days, respectively.
  
  
  METHODS
  The anti-angiogenic actions of pioglitazone, a full PPAR-γ agonist, and telmisartan were firstly assessed in vitro by an aortic ring assay. Endometriosis-like lesions were induced in the dorsal skinfold chamber or peritoneal cavity and the effects of telmisartan and pioglitazone on their vascularization, immune cell content and growth were studied by intravital fluorescence microscopy, high-resolution ultrasound imaging as well as histological, immunohistochemical and immunofluorescent analyses. Additional quantitative real-time polymerase chain reaction (qRT-PCR) arrays served for gene expression profiling of the lesions. To limit the role of chance, the experiments were conducted under standardized laboratory conditions with appropriate vehicle-treated controls. Statistical significance was accepted for a value of P < 0.05.
  
  
  RESULTS
  Telmisartan inhibited vascular sprout formation of aortic rings more effectively than pioglitazone. Accordingly, endometriosis-like lesions in dorsal skinfold chambers of telmisartan-treated animals exhibited a markedly lower functional microvessel density and blood perfusion. High-resolution ultrasound analyses of peritoneal endometriosis-like lesions revealed that the compound inhibited the stromal tissue growth, resulting in a significantly reduced final lesion volume. In contrast, the development of cysts did not differ between the groups. Moreover, telmisartan induced an up-regulation of PPAR-γ and a down-regulation of AT1R proteins in endometriosis-like lesions, which was associated with a decreased density of CD31-positive microvessels, a reduced immune cell content and a lower number of Ki67-positive proliferating cells. qRT-PCR arrays further demonstrated an inhibitory action of telmisartan on the expression of several angiogenic and inflammatory genes.
  
  
  CONCLUSIONS
  Endometriosis-like lesions were induced by syngeneic tissue transplantation into recipient mice without the use of pathological endometriotic tissue of human nature. Therefore, the results obtained in this study may not fully relate to human patients with endometriosis.
  
  
  CONCLUSIONS
  This study demonstrates that telmisartan inhibits vascularization, immune cell content and growth of endometriosis-like lesions. Accordingly, the combined blockade of AT1R and activation of PPAR-γ represents a promising new concept in the development of novel compounds for the treatment of endometriosis.
  
  
  BACKGROUND
  There was no specific funding of this study. The authors have no conflicts of interest to declare.
authors.affiliation: Institute for Clinical and Experimental Surgery, University of Saarland, 66421 Homburg/Saar, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Nenicu
authors.forename: C
authors.initials: C
authors.lastname: Körbel
authors.forename: Y
authors.initials: Y
authors.lastname: Gu
authors.forename: M D
authors.initials: MD
authors.lastname: Menger
authors.forename: M W
authors.initials: MW
authors.lastname: Laschke
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001565:Benzoates / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004715:Endometriosis / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics; D047495:PPAR gamma / Q000819:agonists*; D010532:Peritoneal Diseases / Q000188:drug therapy* / Q000235:genetics; D000077205:Pioglitazone; D000077333:Telmisartan; D045162:Thiazolidinediones / Q000627:therapeutic use; D015854:Up-Regulation
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077333:Telmisartan; D000077205:Pioglitazone
keywords: PPAR-γ; angiogenesis; angiotensin receptor; endometriosis; telmisartan