Role of the integrin αVβ3 in mediating increased smooth muscle cell responsiveness to IGF-I in response to hyperglycemic stress

Clemmons, David R.; Maile, Laura A.; Ling, Yan; Yarber, J.; Busby, Walker H.

doi:10.1016/j.ghir.2007.01.004

Cited by 48Cell Adhesion Molecules ResearchProtein Kinase Regulation and GTPase SignalingProtein Tyrosine Phosphatases

Role of the integrin αVβ3 in mediating increased smooth muscle cell responsiveness to IGF-I in response to hyperglycemic stress

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Clemmons, David R., Maile, Laura A., Ling, Yan, Yarber, J., Busby, Walker H.·2007·Growth Hormone & IGF Research

DOI 10.1016/j.ghir.2007.01.004PMC PMC2366026

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Abstract

Under usual conditions, the role of IGF-I in vascular cell types is to maintain cellular protein synthesis and cell size, and even excess IGF-I does not stimulate proliferation. In pathophysiologic states, such as hyperglycemia, smooth muscle cells (SMC) dedifferentiate and change their responsiveness to IGF-I. During hyperglycemia IGF-I stimulates both SMC migration and proliferation. Our laboratory has investigated the molecular mechanism by which this change is mediated. During hyperglycemia SMC secrete increased concentrations of thrombospondin, vitronectin and osteopontin, ligands for the integrin alphaVbeta3. Activation of alphaVbeta3 stimulates recruitment of a tyrosine phosphatase, SHP-2. Exposure of SMC to IGF-I results in phosphorylation of the transmembrane protein, SHPS-1, which provides a docking site for alphaVbeta3-associated SHP-2. After IGF-I stimulation SHP-2 associates with Src kinase, which associates with the signaling protein Shc. Src phosphorylates Shc, resulting in activation of MAP kinases, which are necessary both for stimulation of cell proliferation and migration. Blocking activation of alphaVbeta3 results in an inability of IGF-I to stimulate Shc phosphorylation. Under conditions of normoglycemia, there are insufficient alphaVbeta3 ligands to recruit SHP-2, and no increase in Shc phosphorylation can be demonstrated in SMC. In contrast, if alphaVbeta3 ligands are added to cells in normal glucose, the signaling events that are necessary for Shc phosphorylation can be reconstituted. Therefore when SMC are exposed to normal glucose they are protected from excessive stimulation of mitogenesis by IGF-I. With hyperglycemia there is a marked increased in alphaVbeta3 ligands and Shc phosphorylation in response to IGF-I is sustained. These findings indicate that in SMC hyperglycemic stress leads to altered IGF-I signaling, which allows the cells to undergo a mitogenic response, and which may contribute to the development of atherosclerosis.

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Hyperglycemia allows IGF-I to stimulate vascular smooth muscle cell proliferation and migration.
“For example, hyperglycemia allows IGF-I to stimulate vascular smooth muscle cell proliferation and migration (53).”
From Diabetes and Cancer (2010) · cites this paper as [53]

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Authors: Clemmons, D. R., Maile, L. A., Ling, Y., Yarber, J., & Busby, W. H.
Affiliations: University of North Carolina at Chapel Hill (US)
Corresponding author: Clemmons, David R.
ORCID: Clemmons, David R.
Venue: Growth Hormone & IGF Research
Publisher: Elsevier BV
Published: 2007-08
Volume: 17
Issue: 4
Pages: 265-270
ISSN: 1096-6374 (ISSN-L)
DOI: 10.1016/j.ghir.2007.01.004
PMC: PMC2366026
OpenAlex: W1969356473
Cited by: 48
References: 43
Citations by year: 2026: 1 · 2025: 2 · 2024: 1 · 2023: 1 · 2021: 4 · 2020: 1 · 2019: 3 · 2018: 2 · 2017: 2 · 2016: 2 · 2015: 1 · 2014: 4 · 2013: 4 · 2012: 5
FWCI: 0.34
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Growth Hormone & IGF Research (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
UNC Libraries
Funders: National Institute on Aging (R01AG002331)
Topics: Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords: integrin αvβ3, IGF-1 signaling, vascular smooth muscle cells, hyperglycemia, Shc phosphorylation, SHP2, Src kinase, MAPK activation, cell proliferation, cell migration, thrombospondin, vitronectin, osteopontin, atherosclerosis, dedifferentiation
MeSH terms: Animals, Blood Glucose, Hyperglycemia, Insulin-Like Growth Factor I, Models, Biological, Stress, Physiological, Myocytes, Smooth Muscle, Integrin alphaVbeta3

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Role of the integrin αVβ3 in mediating increased smooth muscle cell responsiveness to IGF-I in response to hyperglycemic stress

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