VEGF Maintains Maternal Vascular Space Homeostasis in the Mouse Placenta through Modulation of Trophoblast Giant Cell Functions

Abstract

Vascular endothelial growth factor (VEGF) is an angiogenic growth factor that acts primarily on endothelial cells, but numerous studies suggest that VEGF also acts on non-endothelial cells, including trophoblast cells. Inhibition of VEGF signaling by excess production of the endogenous soluble VEGF receptor sFlt1 in trophoblast cells has been implicated in several pregnancy complications. Our previous studies and other reports have shown that VEGF directly regulates placental vascular development and functions and that excess VEGF production adversely affects placental vascular development. Trophoblast giant cells (TGCs) line the maternal side of the placental vasculature in mice and function like endothelial cells. In this study, we specifically examined the effect of excess VEGF signaling on TGC development associated with defective placental vascular development using two mouse models an endometrial VEGF overexpression model and a placenta-specific sFlt1 knockdown model. Placentas of endometrial VEGF-overexpressing dams at embryonic days (E) 11.5 and 14.5 showed dramatic enlargement of the venous maternal spaces in junctional zones. The size and number of the parietal TGCs that line these venous spaces in the placenta were also significantly increased. Although junctional zone venous blood spaces from control and VEGF-overexpressing dams were not markedly different in size at E17.5, the number and size of P-TGCs were both significantly increased in the placentas from VEGF-overexpressing dams. In sFlt1 knockdown placentas, however, there was a significant increase in the size of the sinusoidal TGC-lined, alkaline phosphatase-positive maternal blood spaces in the labyrinth. These results suggest that VEGF signaling plays an important role in maintaining the homeostasis of the maternal vascular space in the mouse placenta through modulation of TGC development and differentiation, similar to the effect of VEGF on endothelial cells in other vascular beds.

Neutrophil depletion in the pre-implantation phase impairs pregnancy index, placenta and fetus development

“…It is expressed in arteriolar smooth muscle, endothelium, trophoblast, uNKs, and decidual cells ( 46 – 49 ). The VEGF expression in the placenta microenvironment has been associated with the modulation of the TGC development and differentiation, and consequent maintenance of the homeostasis of the maternal vascular space in the mouse placenta ( 50 ). Additionally, placental VEGF has related to the modulation of metalloproteinase 2 and 9, which play a role in the endometrial tissue remodeling at implantation ( 51 ), decidualization ( 52 ), and trophoblast invasiveness ( 53 , 54 ).…”

Effect of Rhodomyrtus tomentosa Hassk. on HIF1α and VEGF expressions on hypertension placental

“…When compared to the control group, VEGF positive expression in all pathological groups showed a higher intensity of reactivity. The different expressions of VEGF in tissues in the placenta may be related to the hemodynamic changes that occur in this disorder in the context of normal uteroplacental blood flow restoration (Fan et al, 2021). When compared to normal placentas, VEGFR-1 protein expression was higher in pre-eclampsia (PE) placentas.…”

Müller glia-derived exosomal miR-9-3p promotes angiogenesis by restricting sphingosine-1-phosphate receptor S1P1 in diabetic retinopathy

“…Also, we pretreated hRECs with sFlt1 to block the endogenous VEGF signaling and stimulated hRECs with 50 ng/mL VEGF-A for 15 min. 31,32 As shown in Fig- ure 4A, exogenous VEGF-A stimulation brought rapid phosphorylation of AKT, ERK, and VEGFR2, which was augmented by miR-9-3p mimics and partially abolished in the S1P 1 OE group. Furthermore, we noticed that miR-9-3p mimics caused enhanced VEGFR2 internalization in the presence or absence of exogenous VEGF-A stimulation, while the S1P 1 OE group exhibited impaired VEGF-A-induced endocytosis as reflected by decreased colocalization with EEA1, an endosomal marker (Figure 4B).…”