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Induction of smooth muscle cell migration during arteriogenesis is mediated by Rap2

Jochen Pöling1, Marten Szibor, Silvia Schimanski

  • 1Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.

Arteriosclerosis, Thrombosis, and Vascular Biology
|July 9, 2011
PubMed
Abstract

Insights

Rap2, a signaling molecule, is crucial for collateral artery growth (arteriogenesis) by promoting vascular smooth muscle cell migration downstream of FGF receptor-1 signaling. Modulating Rap2 may offer therapeutic strategies.

Area of Science:

  • Cardiovascular Biology
  • Molecular Signaling
  • Vascular Biology

Background:

  • Arteriogenesis is vital for maintaining blood flow during arterial occlusions.
  • Fibroblast Growth Factor (FGF) receptor signaling is key to arteriogenesis, but downstream mediators are poorly understood.

Purpose of the Study:

  • To identify downstream mediators of FGF signaling in arteriogenesis.
  • To investigate the role of Rap2 in fibroblast growth factor-induced vascular smooth muscle cell (VSMC) function and collateral artery growth.

Main Methods:

  • Screening of signaling components activated by FGF-2 in cultured VSMCs.
  • Utilizing small interfering RNAs (siRNAs) to inhibit Rap2 expression.
  • Employing FGF receptor-1 (FGFR1) inhibition strategies (sulfonic acid polymer, dominant-negative FGFR1 adenovirus).
  • Assessing the impact of Rap2 modulation (dominant-negative and constitutive active forms) on arteriogenesis in vivo.

Main Results:

  • Rap2, but not other Ras family members, was significantly upregulated by FGF-2 in VSMCs and in growing collateral arteries.
  • Rap2 inhibition via siRNA did not affect VSMC proliferation but strongly inhibited migration.
  • FGFR1 inhibition blocked Rap2 upregulation and collateral vessel growth.
  • Dominant-negative Rap2 expression inhibited arteriogenesis, while constitutive active Rap2 enhanced it.

Conclusions:

  • Rap2 functions downstream of FGFR1 within the arteriogenic signaling pathway.
  • Rap2 specifically promotes VSMC migration, a critical component of arteriogenesis.
  • Targeting Rap2 presents a potential therapeutic avenue for conditions involving VSMC migration.

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