The effects of angiotensin peptides and angiotensin receptor antagonists on the cell growth and angiogenic activity of GH3 lactosomatotroph cells in vitro

Abstract

The local renin-angiotensin system (RAS) is present in the pituitary gland, and inhibitory effects of angiotensins on the lactosomatotroph (GH3) cell growth have been revealed. The aim of this study was to examine the influence of various angiotensin peptides and angiotensin AT1, AT2, and AT4 receptors antagonists on the cell proliferation, viability, and VEGF secretion in pituitary lactosomatotroph GH3 cell culture in order to identify receptors involved in antiproliferative effects of angiotensins on GH3 tumor cells. Cell viability and proliferation using Mosmann method and BrdU incorporation during DNA synthesis, and VEGF secretion using ELISA assay were estimated. The inhibitory effects of ang II, ang IV, and ang 5-8 on the cell viability and BrdU incorporation in GH3 culture were not abolished by AT1, AT2, and AT4 receptors antagonists. Ang II, as well as ang III and ang IV at lower concentrations stimulated the secretion of VEGF in GH3 cell culture. The secretion of VEGF was inhibited by ang III and ang IV at higher concentrations. AT1 and AT2 receptors antagonists prevented the proangiogenic effects of ang II. Ang II, ang IV, and ang 5-8 decrease the cell number and proliferation in GH3 cell culture independently of the AT1, AT2, and AT4 receptors. These peptides affect also secretion of VEGF in culture examined. Both the AT1 and AT2 receptors appear to mediate the proangiogenic effects of ang II.

Angiotensin II and Angiotensin Receptors 1 and 2—Multifunctional System in Cells Biology, What Do We Know?

“…All tested antagonists of ATRs (losartan-AT1R antagonist; PD123319-AT2R antagonist; divalinal-AT4R antagonist) were unable to prevent the decrease of total number of the GH3 cells and their proliferation induced by angiotensins. This outcome suggests that growth inhibition induced by angiotensins is not correlated with tested ATRs [56].…”

“…Addition of AT1R and AT2R antagonists and ACE inhibitor caused diminished the number of VEGF-positive blood vessels [54]. Those outcomes suggested that RAS takes part in stimulation of angiogenesis by induction of VEGF secretion acting by AT1R and AT2R in estrogen-induced adenoma [56]. In another study, the influence of Ang IV on VEGF secretion in GH3 cells was additionally tested.…”

“…Many studies revealed correlation between angiotensin and proliferation of pituitary gland cells [50][51][52][53][54][55][56][57][58]. Moreover, Ang II was observed to induce proliferation of mouse spleen lymphocytes in vitro.…”

Comparative effects of angiotensin II and angiotensin-(4-8) on blood pressure and ANP secretion in rats

“…Ang-(4-8) is found in the circulation but there are a few reports about the biological function of Ang-(4-8) [ 10 29 ]. Different behavioral effects of Ang II and Ang-(4-8) have been reported in rats [ 29 ] and Ang-(5-8) has been reported to inhibit GH3 rat pituitary tumor cell proliferation independent of both MAPK p44/42 and MAPK p38 [ 30 ]. In the present study, therefore, we investigated the effects of Ang (4-8) on ANP secretion using isolated perfused rat atria.…”

Effects of angiotensin (5-8) microinfusions into the ventrolateral periaqueductal gray on defensive behaviors in rats

“…In fact, Ang (5-8) elicits small or no changes of cardiovascular parameters compared to Ang II [8]. However, a recent report showed that Ang (5)(6)(7)(8) is effective in the regulation of cellular proliferation [50]. Importantly, we have previously demonstrated that Ang (5)(6)(7)(8) contains the smallest amino acid sequence that is necessary and sufficient to elicit a strong, dose-dependent and region-specific modulation of antinociceptive effect upon injection into the vlPAG [8].…”