Epidermal Growth Factor Induces Vasoconstriction Through the Phosphatidylinositol 3-Kinase-Mediated Mitogen-Activated Protein Kinase Pathway in Hypertensive Rats

Kim, Junghwan; Lee, Chang-Kwon; Park, Hyojun; Kim, Hyo Jin; So, Hyun Ha; Lee, Keun Sang; Lee, Hwan Myung; Roh, Hui Yul; Choi, Wahn Soo; Park, Tae Kyu; Kim, Bokyung

doi:10.1254/jphs.fp0060021

Cited by 42 publications

(35 citation statements)

References 36 publications

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“…In contrast, we found that the activity of Syk, but not that of Akt, in the resting state, was greater in cells from hypertensive rats compared with cells from normotensive rats. Previously, we reported that the PI3K-related MAPK pathway was increased in vascular smooth muscle in hypertensive rats and this was correlated with increases in vascular responses [40, 41]. These results suggest that the altered vascular responses to sVCAM-1 in hypertension can come from the hypertension-associated increase in plasma levels of VCAM-1 or intracellular signal transmission in smooth muscle cells, but not the expression of VLA-4α receptor.…”

Section: Discussionmentioning

confidence: 69%

Soluble Form of Vascular Cell Adhesion Molecule 1 Induces Migration and Proliferation of Vascular Smooth Muscle Cells

Lee¹,

Kim²,

Won³

et al. 2008

J Vasc Res

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Background: Serum levels of soluble vascular cell adhesion molecule 1 (sVCAM-1) shed from its membrane-bound form are elevated in hypertension. This study clarified the effects of sVCAM-1 on vascular responses in rat aortic smooth muscle cells (RASMCs). Methods: Boyden chamber, 5-bromo-2′-deoxyuridine incorporation and ex vivo aortic ring assays for migration and proliferation, and Western blot for the kinase activity were used. Results: Spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats were compared functionally. sVCAM-1 increased RASMC migration and proliferation, which were greater in SHR compared with WKY rats. RASMCs expressed the very late antigen 4α receptor integrin with no difference between SHR and WKY rats. Inhibitors of phosphoinositide kinase 3 (PI3K) and spleen tyrosine kinase (Syk) and small interference RNA-Syk abolished the sVCAM-1-induced migration, proliferation and phosphorylation of focal adhesion kinase. The phosphorylation of Syk was significantly greater in RASMCs from SHR than from WKY rats. sVCAM-1 increased aortic sprout outgrowth, which was inhibited by inhibitors of PI3K and Syk. Conclusions: This study suggests that sVCAM-1 promotes the RASMC migration and proliferation via the focal adhesion kinase pathway regulated by Syk and PI3K, and the altered sVCAM-1-induced responses during hypertension are closely associated with the increments in intracellular signal transmission.

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Section: Discussionmentioning

confidence: 69%

Soluble Form of Vascular Cell Adhesion Molecule 1 Induces Migration and Proliferation of Vascular Smooth Muscle Cells

Lee¹,

Kim²,

Won³

et al. 2008

J Vasc Res

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“…Increased MMP activity, HB-EGF shedding, and EGFR activation have been linked to vasoconstriction caused by G protein-coupled receptor agonists phenylephrine and endothelin-1 (7,16) and increased intravascular pressure (31). In addition, exogenous HB-EGF caused constriction of rat mesenteric arteries (16), and EGF-induced contraction was greatly enhanced in aorta isolated from hypertensive rats (14,26). Our present findings are also consistent with our previous work demonstrating that OxyHb-induced vasoconstriction of smalldiameter cerebral arteries involves tyrosine kinase activation leading to K V channel internalization (22).…”

Section: Discussionmentioning

confidence: 99%

Heparin-binding EGF-like growth factor mediates oxyhemoglobin-induced suppression of voltage-dependent potassium channels in rabbit cerebral artery myocytes

Koide¹,

Penar²,

Tranmer³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Koide M, Penar PL, Tranmer BI, Wellman GC. Heparinbinding EGF-like growth factor mediates oxyhemoglobin-induced suppression of voltage-dependent potassium channels in rabbit cerebral artery myocytes. Am J Physiol Heart Circ Physiol 293: H1750-H1759, 2007. First published June 8, 2007; doi:10.1152/ajpheart.00443.2007 can suppress voltage-dependent K ϩ channel (KV) currents through protein tyrosine kinase activation, which may contribute to cerebral vasospasm following subarachnoid hemorrhage. Here we have tested the hypothesis that shedding of heparin-binding EGF-like growth factor (HB-EGF) and the resulting activation of the tyrosine kinase EGF receptor (EGFR) underlie OxyHb-induced K V channel suppression in the cerebral vasculature. With the use of the conventional whole cell patch-clamp technique, two EGFR ligands, EGF and HB-EGF, were found to mimic OxyHb-induced KV suppression in rabbit cerebral artery myocytes. KV current suppression by OxyHb or EGF ligands was eliminated by a specific EGFR inhibitor, AG-1478, but was unaffected by PKC inhibition. that specifically interfere with HB-EGF signaling eliminated OxyHbinduced K V suppression, suggesting that HB-EGF is the EGFR ligand involved in this pathway. HB-EGF exists as a precursor protein that, when cleaved by matrix metalloproteases (MMPs), causes EGFR activation. MMP activation was detected in OxyHb-treated arteries by gelatin zymography. Furthermore, the MMP inhibitor (GM-6001) abolished OxyHb-induced KV current suppression. We also observed KV current suppression due to EGFR activation in human cerebral artery myocytes. In conclusion, these data demonstrate that OxyHb induces MMP activation, causing HB-EGF shedding and enhanced EGFR activity, ultimately leading to KV channel suppression. We propose that EGFR-mediated KV suppression contributes to vascular pathologies, such as cerebral vasospasm, and may play a more widespread role in the regulation of regional blood flow and peripheral resistance. vascular smooth muscle; growth factors; subarachnoid hemorrhage; tyrosine kinase VOLTAGE-DEPENDENT DELAYED rectifier K ϩ (K V ) channels play an important role in the maintenance of vascular smooth muscle membrane potential and the regulation of arterial diameter (13,35). A reduction in K V channel activity and/or a decrease in K V channel expression in vascular smooth muscle would promote membrane potential depolarization, increased Ca 2ϩ influx via voltage-dependent Ca 2ϩ channels, and vasoconstriction (27). Decreased K V currents have been linked to a number of endogenous and exogenous vasoconstrictors, and K V current suppression has been implicated in systemic and pulmonary hypertension, as well as cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) (22,24,42,49). A large body of evidence suggests that the blood component oxyhemoglobin (OxyHb) contributes to SAH-induced vasoconstriction (3), and our laboratory has recently reported that OxyHb suppresses K V currents in cerebral artery myocytes via a mechanism involving enhanced prote...

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“…Furthermore, the mineralocorticoid deoxycorticosterone acetate (DOCA) can also lead to changes in vascular function with increased basal tone and EGF-induced contraction in hypertensive DOCA-salt rats. Inhibition of PI3kinase and the use of the EGFR kinase inhibitor AG1478 suppressed these alterations in the vasculature [28]. Additionally, an increase in EGFR-mRNA levels accompanied by an EGFinduced arterial contraction has been reported in hypertensive rats [29,30].…”

Section: Physiological Effectsmentioning

confidence: 95%

Mineralocorticoid receptor signaling: Crosstalk with membrane receptors and other modulators

2014

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Epidermal Growth Factor Induces Vasoconstriction Through the Phosphatidylinositol 3-Kinase-Mediated Mitogen-Activated Protein Kinase Pathway in Hypertensive Rats

Cited by 42 publications

References 36 publications

Soluble Form of Vascular Cell Adhesion Molecule 1 Induces Migration and Proliferation of Vascular Smooth Muscle Cells

Soluble Form of Vascular Cell Adhesion Molecule 1 Induces Migration and Proliferation of Vascular Smooth Muscle Cells

Heparin-binding EGF-like growth factor mediates oxyhemoglobin-induced suppression of voltage-dependent potassium channels in rabbit cerebral artery myocytes

Mineralocorticoid receptor signaling: Crosstalk with membrane receptors and other modulators

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