Pregnancy augments uteroplacental vascular endothelial growth factor gene expression and vasodilator effects

Abstract

This study examined a potential role for vascular endothelial growth factor (VEGF) in uterine artery remodeling and vasodilation during pregnancy. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect VEGF mRNA in uterine tissues from nonpregnant (NP), midpregnant (MP, 15-16 days), and late-pregnant (LP, 19-21 days) rats and in placentas from MP and LP rats. VEGF mRNA levels in uteri and placentas were determined by Northern blotting, and the vasorelaxant activity of recombinant human VEGF (rh-VEGF) was tested and compared in isolated uterine arteries from LP and NP animals. VEGF120 and VEGF164 were the major isoforms detected in uterine tissues; all members of the VEGF family (VEGF120, VEGF164, VEGF188, and VEGF205) were expressed in LP placentas. VEGF mRNA levels increased 60% in MP and 80% in LP above those in NP (P < 0.05) in uterine tissues; VEGF mRNA levels were also detectable in placentas and elevated approximately fivefold in LP vs. MP tissues (P < 0.01). Phenylephrine-preconstricted uterine arcuate arteries (NP and LP) dilated in response to rhVEGF, an effect that was completely abolished by endothelial denudation or pretreatment with genistein, a tyrosine kinase inhibitor. The magnitude of dilation to an intermediate concentration of rhVEGF (1 nM) was greater in LP than in NP vessels (55 +/- 8 vs. 24 +/- 11%; P < 0.05), and this effect was diminished comparably in both groups (approximately 60% by N omega-nitro-L-arginine, an inhibitor of nitric oxide synthesis. These results suggest that VEGF may play a role in the vascular remodeling and vasodilation that lead to decreased uterine vascular resistance and increased uterine blood flow during pregnancy.

Vasodilation to Vascular Endothelial Growth Factor in the Uterine Artery of the Pregnant Rat Is Blunted by Low Dietary Protein Intake

“…It therefore appears that VEGF-induced PGI 2 production predominates in the rat uterine artery. Like Ni et al (16), we also found an NO-mediated component of VEGF-induced relaxation in the rat uterine artery. However, the magnitude was less in our study, and this contrasting result with that of Ni et al (16) may be attributed to a difference in the experimental protocol used.…”

“…-nitro-L-arginine is known to be a potent nonselective NO synthase inhibitor compared with other arginine analogs (30); therefore, greater NO inhibition would be expected in the study by Ni et al (16). The differences in NO synthase inhibition of VEGF-induced relaxation between studies may thus be attributed to either a difference in concentration or type of inhibitor used.…”

“…Pregnancy is associated with greater serum concentrations of VEGF in humans (15) and VEGF mRNA in the uterine tissue of the rat (17,18), with an increase in the response to VEGF in the uterine artery (16). It therefore seems reasonable to propose that VEGF plays an important role in dilation of the uterine The effect of L-NAME on the response to ACh of the uterine artery in the 18% (q: without inhibitors, n ϭ 7; ': with L-NAME, n ϭ 5) and the 9% casein groups (⅙: without inhibitors, n ϭ 6; : with L-NAME, n ϭ 6).…”

“…Recently it has been reported in the rat that VEGF mRNA levels increase in the uterine tissue in pregnancy (16). In humans, it has been shown that the maternal plasma concentration of VEGF is increased during pregnancy (17,18).…”

Expression of vascular endothelial growth factor receptor types 1, 2 and 3 in placenta from pregnancies complicated by hypertensive disorders

“…However, there are some discrepancies in the data reported. In particular, in some studies a decrease in the placental expression of VEGF-A and/or its receptors was Ni et al 1997;Torry and Torry 1997;Vuorela et al 1997;Kingdom et al 2000;Favier and Corvol 2001 VEGF-B 48 VEGFR-1/Flt-1 De Vries et al 1992;Klagsbrun and D'Amore 1996;Vuorela et al 1997 VEGF-C 24 VEGFR-2/Flk-1 Joukov et al 1996;Klagsbrun and D'Amore VEGFR-3/Flt-4 1996;Vuorela et al 1997;Enholm et al 1998 VEGF-D 16 VEGFR-2/Flk-1 Gu et al 2006 VEGFR-3/Flt-4 PLGF 50 VEGFR-1/Flt-1 Maglione et al 1991;De Vries et al 1992 VEGF, vascular endothelial growth factor; PLGF, placental growth factor.…”