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VEGF‐A inhibits agonist‐mediated Ca 2+ responses and activation of IK Ca channels in mouse resistance artery endothelial cells
Author(s) -
Ye Xi,
Beckett Taylor,
Bagher Pooneh,
Garland Christopher J.,
Dora Kim A.
Publication year - 2018
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp275793
Subject(s) - vasodilation , endocrinology , medicine , kinase insert domain receptor , vascular endothelial growth factor , hyperpolarization (physics) , endothelium , angiogenesis , vascular endothelial growth factor a , agonist , endothelial stem cell , vascular permeability , biology , receptor , chemistry , microbiology and biotechnology , biochemistry , in vitro , vegf receptors , organic chemistry , nuclear magnetic resonance spectroscopy
Key points Prolonged exposure to vascular endothelial growth factor A (VEGF‐A) inhibits agonist‐mediated endothelial cell Ca 2+ release and subsequent activation of intermediate conductance Ca 2+ ‐activated K + (IK Ca ) channels, which underpins vasodilatation as a result of endothelium‐dependent hyperpolarization (EDH) in mouse resistance arteries. Signalling via mitogen‐activated protein/extracellular signal‐regulated kinase kinase (MEK) downstream of VEGF‐A was required to attenuate endothelial cell Ca 2+ responses and the EDH‐vasodilatation mediated by IK Ca activation. VEGF‐A exposure did not modify vasodilatation as a result of the direct activation of IK Ca channels, nor the pattern of expression of inositol 1,4,5‐trisphosphate receptor 1 within endothelial cells of resistance arteries. These results indicate a novel role for VEGF‐A in resistance arteries and suggest a new avenue for investigation into the role of VEGF‐A in cardiovascular diseases.Abstract Vascular endothelial growth factor A (VEGF‐A) is a potent permeability and angiogenic factor that is also associated with the remodelling of the microvasculature. Elevated VEGF‐A levels are linked to a significant increase in the risk of cardiovascular dysfunction, although it is unclear how VEGF‐A has a detrimental, disease‐related effect. Small resistance arteries are central determinants of peripheral resistance and endothelium‐dependent hyperpolarization (EDH) is the predominant mechanism by which these arteries vasodilate. Using isolated, pressurized resistance arteries, we demonstrate that VEGF‐A acts via VEGF receptor‐2 (R2) to inhibit both endothelial cell (EC) Ca 2+ release and the associated EDH vasodilatation mediated by intermediate conductance Ca 2+ ‐activated K + (IK Ca ) channels. Importantly, VEGF‐A had no direct effect against IK Ca channels. Instead, the inhibition was crucially reliant on the downstream activation of the mitogen‐activated protein/extracellular signal‐regulated kinase kinase 1/2 (MEK1/2). The distribution of EC inositol 1,4,5‐trisphosphate (IP 3 ) receptor‐1 (R1) was not affected by exposure to VEGF‐A and we propose an inhibition of IP 3 R1 through the MEK pathway, probably via ERK1/2. Inhibition of EC Ca 2+ via VEGFR2 has profound implications for EDH‐mediated dilatation of resistance arteries and could provide a mechanism by which elevated VEGF‐A contributes towards cardiovascular dysfunction.