Placental growth factor blunts uterine artery responses to angiotensin II

Abstract

Objective: Changes in maternal serum concentration of placental growth factor (PlGF) and vascular response to intravascular infusion of Angiotensin II (Ang II) follow a bell-shaped curve pattern during gestation. This study evaluates the effects of PlGF and soluble vascular endothelial growth factor receptor-1 (sFlt-1) on responses of human uterine arteries (UA) to Ang II.

Design: Experimental.

Setting: Baylor College of Medicine and Texas Children's Hospital-Pavilion for Women.

Sample: Uterine arteries samples (n = 14) were obtained from normotensive women undergoing caesarean hysterectomy at ≥32 weeks.

Methods: Uterine arteries rings were incubated with (1) Krebs solution; (2) PlGF at 1.45, 14.5, and 500 pg/ml; (3) sFlt-1 at 2 ng/ml; and (4) a combination of sFlt-1, and PlGF. Dose-contraction responses to Ang II were determined in UA rings incubated in the above-mentioned conditions. Responses were also measured in presence of L-NAME or inhibitors of endothelium-derived hyperpolarising factor: apamine and charybdotoxin. The t-test was used for comparisons.

Main outcome measure: Changes in vascular reactivity of UA rings.

Results: PlGF blunted (P = 0.03) and sFlt-1 increased (P <0.01) the UA maximum responses to Ang II. A combination of sFlt-1 and PlGF blunted UA responses to Ang II (P < 0.05). l-NAME, apamine, and charybdotoxin reversed the relaxation effects of PlGF on UA responses to Ang II (P < 0.05).

Conclusions: PlGF contributes to the blunted vascular response to Angiotensin II during normotensive pregnancies and sFlt-1 appears to attenuate this effect. PlGF and sFlt-1 may contribute to the regulation of vascular tone during pregnancy by altering the vascular response to Angiotensin II.

Funding: Baylor College of Medicine.

Tweetable abstract: Placental growth factor and soluble vascular endothelial growth factor receptor-1 modulate the uterine artery response to Angiotensin II in normotensive pregnant women.

Keywords: Angiotensin II; placental growth factor; response; sFlt-1; vascular.

Figure 1.

Uterine artery (UA) rings incubated for 24 hours with 0.1 nM and 33 nM of placental growth factor (PlGF, hollow circles and squares) had lower maximum responses to Angiotensin II (Ang II) compared to UA rings incubated with Krebs solution (solid circles) (Figures 1a and 1b); Similarly, lower maximum responses were found in UA rings incubated for 24 hours with 1 nM of PlGF (hollow triangles, Figure 1a) but the difference was not statistically significant. UA responses to bradykinin confirmed endothelial integrity (Figure 1d). All the vessels were normalized before the experiments. An average start tension of 13 micro Newtons was applied to the vessels.

Figure 2.

Uterine artery (UA) rings incubated for 24 hours with physiological concentration of the soluble form of vascular endothelial growth factor receptor-1 (sFlt-1, hollow squares) had higher maximum responses to Angiotensin II (Ang II) compared to controls (solid circles).

Figure 3.

Uterine artery (UA) rings incubated with a combination of placental growth factor (PlGF) and the soluble form of vascular endothelial growth factor receptor-1 (sFlt-1) at high concentrations, attenuated the PlGF effects on uterine artery responses to Angiotensin II (Ang II), (p<0.05; Figures 3a, 3b and 3c). : The sFlt-1/PlGF ratios are as follows: 1.6 (PlGF: 6 ng/ml and sFlt-1: 10 ng/ml); 5.5 (PlGF: 18 ng/ml and sFlt-1: 100 ng/ml); and 33.3 (PlGF: 30 ng/ml and sFlt-1: 1000 ng/ml. In all experiments, UA responses to bradykinin confirmed endothelial integrity (Figure 4d).

Figure 4.

Nitro L-arginine methylester (L-NAME, an inhibitor of nitric oxide synthase, hollow circles), and inhibitors of Endothelium-Derived Hyperpolarizing Factor (EDHF): Apamine (APA) and Charybdotoxin (CHX) (hollow squares) reversed the relaxation effects of PlGF on uterine artery rings responses to Angiotensin II (Ang II) (solid squares).