PDGF-induced migration of vascular smooth muscle cells is inhibited by heme oxygenase-1 via VEGFR2 upregulation and subsequent assembly of inactive VEGFR2/PDGFRβ heterodimers

Caroline Cheng; Remco A Haasdijk; Dennie Tempel; Wijnand K den Dekker; Ihsan Chrifi; Lau A J Blonden; Esther H M van de Kamp; M de Boer; Petra E Bürgisser; Annemarie Noorderloos; Joost A P Rens; Timo L M ten Hagen; Henricus J Duckers

doi:10.1161/ATVBAHA.112.245530

PDGF-induced migration of vascular smooth muscle cells is inhibited by heme oxygenase-1 via VEGFR2 upregulation and subsequent assembly of inactive VEGFR2/PDGFRβ heterodimers

Caroline Cheng, Remco A Haasdijk, Dennie Tempel, Wijnand K den Dekker, Ihsan Chrifi, Lau A J Blonden, Esther H M van de Kamp, M de Boer, Petra E Bürgisser, Annemarie Noorderloos, Joost A P Rens, Timo L M ten Hagen, Henricus J Duckers

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

OBJECTIVE: In cardiovascular regulation, heme oxygenase-1 (HO-1) activity has been shown to inhibit vascular smooth muscle cell (VSMC) proliferation by promoting cell cycle arrest at the G1/S phase. However, the effect of HO-1 on VSMC migration remains unclear. We aim to elucidate the mechanism by which HO-1 regulates PDGFBB-induced VSMC migration.

METHODS AND RESULTS: Transduction of HO-1 cDNA adenoviral vector severely impeded human VSMC migration in a scratch, transmembrane, and directional migration assay in response to PDGFBB stimulation. Similarly, HO-1 overexpression in the remodeling process during murine retinal vasculature development attenuated VSMC coverage over the major arterial branches as compared with sham vector-transduced eyes. HO-1 expression in VSMCs significantly upregulated VEGFA and VEGFR2 expression, which subsequently promoted the formation of inactive PDGFRβ/VEGFR2 complexes. This compromised PDGFRβ phosphorylation and impeded the downstream cascade of FAK-p38 signaling. siRNA-mediated silencing of VEGFA or VEGFR2 could reverse the inhibitory effect of HO-1 on VSMC migration.

CONCLUSIONS: These findings identify a potent antimigratory function of HO-1 in VSMCs, a mechanism that involves VEGFA and VEGFR2 upregulation, followed by assembly of inactive VEGFR2/PDGFRβ complexes that attenuates effective PDGFRβ signaling.

Original language	English
Pages (from-to)	1289-98
Number of pages	10
Journal	Arteriosclerosis, Thrombosis and Vascular Biology
Volume	32
Issue number	5
DOIs	https://doi.org/10.1161/ATVBAHA.112.245530
Publication status	Published - 2012

Keywords

Cell Movement
Cell Proliferation
Heme Oxygenase-1
Humans
Muscle, Smooth, Vascular
Platelet-Derived Growth Factor
RNA, Messenger
Receptor, Platelet-Derived Growth Factor beta
Signal Transduction
Up-Regulation
Vascular Endothelial Growth Factor Receptor-2

Access to Document

10.1161/ATVBAHA.112.245530

Cite this

Cheng, C., Haasdijk, R. A., Tempel, D., den Dekker, W. K., Chrifi, I., Blonden, L. A. J., van de Kamp, E. H. M., de Boer, M., Bürgisser, P. E., Noorderloos, A., Rens, J. A. P., ten Hagen, T. L. M., & Duckers, H. J. (2012). PDGF-induced migration of vascular smooth muscle cells is inhibited by heme oxygenase-1 via VEGFR2 upregulation and subsequent assembly of inactive VEGFR2/PDGFRβ heterodimers. Arteriosclerosis, Thrombosis and Vascular Biology, 32(5), 1289-98. https://doi.org/10.1161/ATVBAHA.112.245530

@article{3d68d7a5e70d489f8a6b4aa4291cd1e2,

title = "PDGF-induced migration of vascular smooth muscle cells is inhibited by heme oxygenase-1 via VEGFR2 upregulation and subsequent assembly of inactive VEGFR2/PDGFRβ heterodimers",

abstract = "OBJECTIVE: In cardiovascular regulation, heme oxygenase-1 (HO-1) activity has been shown to inhibit vascular smooth muscle cell (VSMC) proliferation by promoting cell cycle arrest at the G1/S phase. However, the effect of HO-1 on VSMC migration remains unclear. We aim to elucidate the mechanism by which HO-1 regulates PDGFBB-induced VSMC migration.METHODS AND RESULTS: Transduction of HO-1 cDNA adenoviral vector severely impeded human VSMC migration in a scratch, transmembrane, and directional migration assay in response to PDGFBB stimulation. Similarly, HO-1 overexpression in the remodeling process during murine retinal vasculature development attenuated VSMC coverage over the major arterial branches as compared with sham vector-transduced eyes. HO-1 expression in VSMCs significantly upregulated VEGFA and VEGFR2 expression, which subsequently promoted the formation of inactive PDGFRβ/VEGFR2 complexes. This compromised PDGFRβ phosphorylation and impeded the downstream cascade of FAK-p38 signaling. siRNA-mediated silencing of VEGFA or VEGFR2 could reverse the inhibitory effect of HO-1 on VSMC migration.CONCLUSIONS: These findings identify a potent antimigratory function of HO-1 in VSMCs, a mechanism that involves VEGFA and VEGFR2 upregulation, followed by assembly of inactive VEGFR2/PDGFRβ complexes that attenuates effective PDGFRβ signaling.",

keywords = "Cell Movement, Cell Proliferation, Heme Oxygenase-1, Humans, Muscle, Smooth, Vascular, Platelet-Derived Growth Factor, RNA, Messenger, Receptor, Platelet-Derived Growth Factor beta, Signal Transduction, Up-Regulation, Vascular Endothelial Growth Factor Receptor-2",

author = "Caroline Cheng and Haasdijk, {Remco A} and Dennie Tempel and {den Dekker}, {Wijnand K} and Ihsan Chrifi and Blonden, {Lau A J} and {van de Kamp}, {Esther H M} and {de Boer}, M and B{\"u}rgisser, {Petra E} and Annemarie Noorderloos and Rens, {Joost A P} and {ten Hagen}, {Timo L M} and Duckers, {Henricus J}",

year = "2012",

doi = "10.1161/ATVBAHA.112.245530",

language = "English",

volume = "32",

pages = "1289--98",

journal = "Arteriosclerosis, Thrombosis and Vascular Biology",

issn = "1079-5642",

publisher = "Lippincott Williams & Wilkins",

number = "5",

}

Cheng, C, Haasdijk, RA, Tempel, D, den Dekker, WK, Chrifi, I, Blonden, LAJ, van de Kamp, EHM, de Boer, M, Bürgisser, PE, Noorderloos, A, Rens, JAP, ten Hagen, TLM & Duckers, HJ 2012, 'PDGF-induced migration of vascular smooth muscle cells is inhibited by heme oxygenase-1 via VEGFR2 upregulation and subsequent assembly of inactive VEGFR2/PDGFRβ heterodimers', Arteriosclerosis, Thrombosis and Vascular Biology, vol. 32, no. 5, pp. 1289-98. https://doi.org/10.1161/ATVBAHA.112.245530

PDGF-induced migration of vascular smooth muscle cells is inhibited by heme oxygenase-1 via VEGFR2 upregulation and subsequent assembly of inactive VEGFR2/PDGFRβ heterodimers. / Cheng, Caroline; Haasdijk, Remco A; Tempel, Dennie et al.
In: Arteriosclerosis, Thrombosis and Vascular Biology, Vol. 32, No. 5, 2012, p. 1289-98.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - PDGF-induced migration of vascular smooth muscle cells is inhibited by heme oxygenase-1 via VEGFR2 upregulation and subsequent assembly of inactive VEGFR2/PDGFRβ heterodimers

AU - Cheng, Caroline

AU - Haasdijk, Remco A

AU - Tempel, Dennie

AU - den Dekker, Wijnand K

AU - Chrifi, Ihsan

AU - Blonden, Lau A J

AU - van de Kamp, Esther H M

AU - de Boer, M

AU - Bürgisser, Petra E

AU - Noorderloos, Annemarie

AU - Rens, Joost A P

AU - ten Hagen, Timo L M

AU - Duckers, Henricus J

PY - 2012

Y1 - 2012

N2 - OBJECTIVE: In cardiovascular regulation, heme oxygenase-1 (HO-1) activity has been shown to inhibit vascular smooth muscle cell (VSMC) proliferation by promoting cell cycle arrest at the G1/S phase. However, the effect of HO-1 on VSMC migration remains unclear. We aim to elucidate the mechanism by which HO-1 regulates PDGFBB-induced VSMC migration.METHODS AND RESULTS: Transduction of HO-1 cDNA adenoviral vector severely impeded human VSMC migration in a scratch, transmembrane, and directional migration assay in response to PDGFBB stimulation. Similarly, HO-1 overexpression in the remodeling process during murine retinal vasculature development attenuated VSMC coverage over the major arterial branches as compared with sham vector-transduced eyes. HO-1 expression in VSMCs significantly upregulated VEGFA and VEGFR2 expression, which subsequently promoted the formation of inactive PDGFRβ/VEGFR2 complexes. This compromised PDGFRβ phosphorylation and impeded the downstream cascade of FAK-p38 signaling. siRNA-mediated silencing of VEGFA or VEGFR2 could reverse the inhibitory effect of HO-1 on VSMC migration.CONCLUSIONS: These findings identify a potent antimigratory function of HO-1 in VSMCs, a mechanism that involves VEGFA and VEGFR2 upregulation, followed by assembly of inactive VEGFR2/PDGFRβ complexes that attenuates effective PDGFRβ signaling.

AB - OBJECTIVE: In cardiovascular regulation, heme oxygenase-1 (HO-1) activity has been shown to inhibit vascular smooth muscle cell (VSMC) proliferation by promoting cell cycle arrest at the G1/S phase. However, the effect of HO-1 on VSMC migration remains unclear. We aim to elucidate the mechanism by which HO-1 regulates PDGFBB-induced VSMC migration.METHODS AND RESULTS: Transduction of HO-1 cDNA adenoviral vector severely impeded human VSMC migration in a scratch, transmembrane, and directional migration assay in response to PDGFBB stimulation. Similarly, HO-1 overexpression in the remodeling process during murine retinal vasculature development attenuated VSMC coverage over the major arterial branches as compared with sham vector-transduced eyes. HO-1 expression in VSMCs significantly upregulated VEGFA and VEGFR2 expression, which subsequently promoted the formation of inactive PDGFRβ/VEGFR2 complexes. This compromised PDGFRβ phosphorylation and impeded the downstream cascade of FAK-p38 signaling. siRNA-mediated silencing of VEGFA or VEGFR2 could reverse the inhibitory effect of HO-1 on VSMC migration.CONCLUSIONS: These findings identify a potent antimigratory function of HO-1 in VSMCs, a mechanism that involves VEGFA and VEGFR2 upregulation, followed by assembly of inactive VEGFR2/PDGFRβ complexes that attenuates effective PDGFRβ signaling.

KW - Cell Movement

KW - Cell Proliferation

KW - Heme Oxygenase-1

KW - Humans

KW - Muscle, Smooth, Vascular

KW - Platelet-Derived Growth Factor

KW - RNA, Messenger

KW - Receptor, Platelet-Derived Growth Factor beta

KW - Signal Transduction

KW - Up-Regulation

KW - Vascular Endothelial Growth Factor Receptor-2

U2 - 10.1161/ATVBAHA.112.245530

DO - 10.1161/ATVBAHA.112.245530

M3 - Article

C2 - 22426130

SN - 1079-5642

VL - 32

SP - 1289

EP - 1298

JO - Arteriosclerosis, Thrombosis and Vascular Biology

JF - Arteriosclerosis, Thrombosis and Vascular Biology

IS - 5

ER -

PDGF-induced migration of vascular smooth muscle cells is inhibited by heme oxygenase-1 via VEGFR2 upregulation and subsequent assembly of inactive VEGFR2/PDGFRβ heterodimers

Abstract

Keywords

Access to Document

Fingerprint

Cite this