Antiangiogenic-induced hypertension: the molecular basis of signaling network.
OBJECTIVE
Preeclampsia, a pregnancy-related hypertensive disorder, is one of the leading causes of fetal and maternal death globally. Angiogenic factors including vascular endothelial growth factor (VEGF) are involved in the formation of new blood vessels required for placental development and function. The hallmark of preeclampsia is similar to the toxicities related to antiangiogenesis therapy. VEGF inhibitors or antagonists promote vasoconstriction, hypertension and proteinuria. VEGF plays a role in attenuating hypertension and improving kidney damage in an animal model; however, the mechanisms underlying this effect remain poorly defined. The aim of this paper is to summarize recent advances in VEGF-mediated signaling and the target molecules, and provide new insights into treatment strategies for preeclampsia.


METHODS
This article reviews the English-language literature for pathogenesis of preeclampsia based on VEGF signaling and hypertension.


RESULTS
VEGF activates downstream signaling molecules, including Ca(2+)/CAMKK, Rac1/NOX, ROS/ERK, Ezrin/Calpain/PI3K/Akt, PLCγ/PKC and Src/HSP90. Among these signalings, important pathways for receptor-triggered intracellular signaling are (1) the PI3K/Akt-dependent, (2) the PLCγ-dependent and (3) the ERK/Egr-1-dependent pathway. VEGF is closely involved in receptor-activated signaling events, leading to eNOS-dependent NO synthesis and eNOS-independent endothelial cell proliferation, respectively, and thus modulates vasoactive function and angiogenic response.


CONCLUSIONS
This review highlights the potential role of NO in vasodilation, while stress-related ERK activation might act to strengthen angiogenesis, migration and proliferation. We discuss the similarity between preeclampsia and VEGF-targeted therapy-induced hypertension.
Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan.
Akira
A
Nagai
Toshiyuki
T
Sado
Katsuhiko
K
Naruse
Taketoshi
T
Noguchi
Shoji
S
Haruta
Shozo
S
Yoshida
Yasuhito
Y
Tanase
Taihei
T
Tsunemi
Hiroshi
H
Kobayashi
D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011225:Pre-Eclampsia / Q000139:chemically induced* / Q000378:metabolism; D011247:Pregnancy; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000502:physiology*
D020533:Angiogenesis Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III