Endothelial-Derived Hyperpolarization Factor (EDHF) Contributes to PlGF-Induced Dilation of Mesenteric Resistance Arteries from Pregnant Rats

Abstract

The aim of this study was to investigate the cellular mechanism involved in the potent vasodilatory action of PlGF on mesenteric resistance arteries from pregnant rats. PlGF (3 nM) induced a vasodilation of 64 ± 3.8% that was completely abolished by endothelial denudation. Significant dilation (28 ± 4.0%) remained, however, in the presence of nitric oxide synthase and cyclooxygenase inhibition, and was associated with significant reductions in vascular smooth muscle cell calcium. Absence of dilation in potassium-depolarizing solution (30 mM) confirmed its dependence on endothelial-derived hyperpolarization factor. Subsequent studies established that vasodilation was abolished by pharmacologic inhibition of SK_Ca (apamin) and BK_Ca (iberiotoxin) but not IK_Ca (tram-34) potassium channels. In summary, PlGF acts through the release of a combination of endothelium-derived relaxation factors. Based on the results of potassium channel blockade, we suggest that it induces endothelial hyperpolarization via SK_Ca channel activation; this, in turn, leads to the release of a diffusible mediator that activates vascular smooth muscle BK_Ca channels, hyperpolarization and vasodilation. This is the first study to identify the mechanism for PlGF/VEGFR-1 resistance artery dilation in the pregnant state, whose attenuation likely contributes to the systemic hypertension characteristic of pre- eclampsia.

Maternal Vascular Physiology in Preeclampsia

“…Placental growth factor, which binds to the vascular endothelial growth factor receptor-1, induced endothelial cell hyperpolarization via activation of SK Ca channels in mesenteric arteries from pregnant rats. 42 This hyperpolarization was independent from NO and PGI 2 and was spread to the vascular smooth muscle cells via largeconductance calcium-activated potassium channels (BK Ca ) that were activated by an unknown diffusible factor. 42 The authors posited that in preeclampsia, attenuation of placental growth factor-induced EDH contributes to impaired function of resistance arteries and leads to maternal hypertension.…”

“…42 This hyperpolarization was independent from NO and PGI 2 and was spread to the vascular smooth muscle cells via largeconductance calcium-activated potassium channels (BK Ca ) that were activated by an unknown diffusible factor. 42 The authors posited that in preeclampsia, attenuation of placental growth factor-induced EDH contributes to impaired function of resistance arteries and leads to maternal hypertension. 42 Recent studies suggest the involvement of hydrogen sulfide, a gaseous signaling molecule that induces EDH, 43 in preeclampsia-associated vascular dysfunction.…”

“…42 The authors posited that in preeclampsia, attenuation of placental growth factor-induced EDH contributes to impaired function of resistance arteries and leads to maternal hypertension. 42 Recent studies suggest the involvement of hydrogen sulfide, a gaseous signaling molecule that induces EDH, 43 in preeclampsia-associated vascular dysfunction. Circulating hydrogen sulfide is reduced in pregnant women with preeclampsia, 44 and expression of cystathionine-β-synthase, the enzyme that is involved in desulfuration of l-cysteine into hydrogen sulfide, is attenuated in endothelial cells stimulated with plasma from pregnancies with preeclampsia.…”

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

“…38). In contrast, endothelium-derived hyperpolarizing factor (83,86,114,123,124,126,164,175), K ATP ϩ channel activation (100) and endothelium-derived relaxing factor (EDRF) or nitric oxide (NO) (175) autocoid was implicated in the vasodilatory phenomena of pregnancy (28,43). Later, evidence for increased NO biosynthesis was reported in gravid rats (37).…”

The SK3 channel promotes placental vascularization by enhancing secretion of angiogenic factors

“…First, activation of the endothelial SK3 channel induces release of endothelium-derived hyperpolarizing factor (EDHF), causing vasodilation (9,30). Second, in rat mesenteric arteries, SK3 activity modulates PlGF levels, thereby activating the EDHF pathway (19). Third, in pregnant sheep uterine arteries, the SK3 channel is regulated by hypoxia (34), a known driving force of angiogenesis (2).…”