The objectives of this study were to determine whether placental growth factor (PlGF) exerts a vasodilatory effect on rat uterine vessels (arcuate arteries and veins) and to examine regional differences in reactivity by comparing these responses to those of comparably sized mesenteric vessels. We also sought to examine and compare its effects on human uterine and subcutaneous vessels. All vessels were studied in vitro, under pressurized (rat) or isometric wire-mounted (human) conditions, and exposed to a range of PlGF concentrations. Inhibitors of nitric oxide and prostaglandin synthesis were included in an effort to understand the causal mechanism(s). In rat uterine arteries, the effects of receptor inhibition and activation using selective ligands for VEGFR-1 (PlGF) vs. VEGFR-2 (VEGF-E) were determined, and real-time RT-PCR was performed to evaluate the effect of pregnancy on relative abundance of VEGFR-1 and VEGFR-2 message in the vascular wall. PlGF was a potent vasodilator of all vessels studied, with greatest sensitivity observed in rat uterine arteries. Pregnancy significantly augmented dilator sensitivity to PlGF, and this effect was associated with selective upregulation of VEGFR-1 message in the pregnant state. The contribution of nitric oxide was appreciable in rat and human uterine arteries, with lesser effects in rat uterine veins and mesenteric arteries, and with no observable effect in human subcutaneous vessels. Based on these results, we conclude that PlGF is a potent vasodilator of several vessel types in both humans and rats. Its potency and mechanism vary with physiological state and vessel location and are mediated solely by the VEGFR-1 receptor subtype. Gestational changes in the uterine circulation suggest that this factor may play a role in modulating uterine vascular remodeling and blood flow during the pregnant state.

The study was supported by the following grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD K12HD047018 (W.M.), NICHD K12HD001271 (L.A.K.). The authors have no competing interests.

No abstract

No abstract

Background: Transfer of molecular signals from veins to adjacent arteries is an established mechanism of vascular communication in the uterine circulation, which ultimately depends on venous permeability. This study tests the hypotheses that: (1) uterine veins are permeable to intravenous solutes, using a 3-kDa dextran tracer and (2) this permeability is enhanced in response to vascular endothelial growth factor (VEGF). Additionally, the involvement of nitric oxide (NO), calcium, and the phospholipase C-protein kinase C (PLC-PKC) cascade in VEGF-enhanced permeability were investigated, and the impact of pregnancy-induced uterine vascular remodeling on permeability was evaluated. Methods: Studies utilized fluorimetry to quantitate solute flux in isolated segments of rat uterine vein as a function of endothelial surface area and time under basal and VEGF-stimulated conditions. VEGF signaling was probed using NO synthase inhibition (L-NNA), calcium channel blockade (lanthanum chloride) and withdrawal (calcium-free solution), and inhibitors of the PLC-PKC cascade (U-73122 and chelerythrine chloride, respectively). Gestational effects were assessed using vessels from late pregnant (day 20) rats. Results: Basal flux (control) in nonpregnant animals was 26 ± 2.5 molecules/µm²/min × 1,000 and was increased significantly by VEGF in a concentration-dependent manner (1 nM ≈ 3.3-fold, 10 nM ≈ 4.6-fold). Inhibition of PLC, PKC, and calcium signaling, but not NO, attenuated the response to VEGF. Gestation significantly increased flux (78 ± 9.3 molecules/µm²/min × 1,000), and maintained responsiveness to VEGF. Conclusions: These results demonstrate uterine venous permeability to intermediate-sized solutes through a VEGF-sensitive pathway involving calcium and PLC-PKC, but not NO, and further substantiate a role for veno-arterial communication in uterine blood flow regulation during pregnancy.