Contractility of Placental Vascular Smooth Muscle Cells in Response to Stimuli Produced by the Placenta: Roles of ACE vs. Non-ACE and AT1 vs. AT2 in Placental Vessel Cells

Abstract

Our previously published work has shown that non-ACE angiotensin II (Ang II) generating system is dominate in the placenta and may play a critical role in regulation of placental vascular contractile function. In the present study, using a collagen gel contraction assay we further studied contractility of placental vascular smooth muscle cells (VSMCs) in response to factors produced by preeclamptic (PE) placentas. Placental VSMCs/type-1 collagen gels were incubated with PE placental conditioned medium in the presence or absence of inhibitors or receptor blockers. Captopril (an ACE inhibitor), chymostatin (a non-ACE chymase inhibitor), losartan (an AT1 receptor blocker) and PD123,319 (an AT2 receptor blocker) were used to study the specific ACE vs. non-ACE and AT1 vs. AT2 effects on placental VSMC contractility, respectively. Our results showed that chymostatin, but not captopril, and PD123,319, but not losartan, significantly attenuated placental VSMC/collagen gel contraction, p < 0.01, respectively. The inhibitory effects of chymostatin and PD123,319 were dosedependent. Our results suggest that chymase, a non-ACE Ang II generating enzyme, may contribute significantly to Ang II generated in the placenta vascular tissue and that the AT2 receptor may play an important role in the regulation of Ang II induced contractility of placental VSMCs. These results provide new insights into Ang II generation and Ang II receptor regulation of vessel contractile function in the placental vasculature. These results also suggest the potential role of increased chymase activity and altered AT2 receptor function in placental related pregnancy disorders such as preeclampsia and IUGR.

Differential expression of angiotensin II type 1 and type 2 receptors at the maternal–fetal interface: potential roles in early placental development

“…The localisation of AGTR2 to villous cytotrophoblasts and Hofbauer cells, both of which are sparser per unit area of term placenta, may explain the failure of previous studies to detect the receptor in whole tissue placental homogenates later in gestation (Cooper et al 1999, Anton et al 2008. Its presence in human placenta is consistent with the observation of AGTR2-dependent contraction of term chorionic plate artery vascular smooth muscle (Benoit et al 2008) and low but significant AGTR2 inhibitory binding of radiolabelled Ang II to term placenta (Li et al 1998).…”

Human placenta as an ex vivo vascular model for neurointerventional research

“…The smooth muscle constriction may be triggered by the release of angiotensin II from the placenta 13. In our observation, the pressurized infusion of Ringer's solution for 10–15 min can also restore the normal luminal size of the vessels.…”

GPCRs as potential therapeutic targets in preeclampsia

“…These studies suggest that specific AT2 agonists might be used to ameliorate hypertension in preeclampsia. However, one possible caveat is an opposing effect in the placental circulation: an in vitro study using placental vascular smooth muscle cells (VSMC) suggested that AT2 mediates VSMC contraction in response to preeclamptic placenta-conditioned media [52]. Therefore, pharmacological activation of AT2 signalling may restrict placental blood flow specifically; clearly an undesirable outcome in preeclampsia.…”