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Cardiovascular Research Advance Access first published online on August 31, 2009
This version [Corrected Proof] published online on September 16, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp288
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Flt-1 expression influences apoptotic susceptibility of vascular smooth muscle cells through the NF-{kappa}B/IAP-1 pathway

Augusto Orlandi1,*, Amedeo Ferlosio1, Gaetano Arcuri2, Maria Giovanna Scioli1, Sandro De Falco3 and Luigi Giusto Spagnoli1

1 Department of Biopathology and Image Diagnostics, Anatomic Pathology, Tor Vergata University of Rome, Via Montpellier, Rome 00133, Italy
2 Experimental Medicine and Biochemical Sciences, Tor Vergata University of Rome, Via Montpellier, Rome 00133, Italy
3 Institute of Genetics and Biophysics, CNR, Via Pietro Castellino 111, Naples 80131, Italy

* Corresponding author. Tel: +39 06 20903960, Fax: +39 06 20902209, Email: orlandi{at}uniroma2.it

Aims: Flt-1 is an fms-like tyrosine kinase receptor which binds to vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). Ligand activation and blocking of flt-1 influence several vascular smooth muscle cell (SMC) functions, including apoptotic susceptibility. However, downstream signal transduction pathways by which flt-1 regulates SMC apoptosis have still to be investigated.

Methods and results: Flt-1 expression and apoptosis in Wistar rat aortic intimal cells 15 days after ballooning were studied by immunohistochemistry, cytometry, cell sorting, western blotting, and PCR. Anti-flt1 blocking antibody effects were compared with those of anti-PlGF and anti-VEGF antibodies. Rat aortic intimal cells 15 days after injury exhibited increased flt-1 protein and mRNA and lower smooth muscle markers compared with normal media SMCs. Immunoreactivity for flt-1 protein was also observed in apoptotic intimal cells. Anti-flt-1 (EC50 = 16.5 ng/mL) and anti-PlGF (EC50 = 20.5 ng/mL) antibodies added to intimal cultures reduced serum-deprived apoptosis but not serum- and PDGF-BB-induced proliferation; the anti-VEGF antibody was ineffective. Sorted flt-1+ cells were more clonogenic than flt-1– and whole intimal SMC populations. Increased nuclear factor-kappaB (NF-{kappa}B) and inhibitor of apoptosis protein-1 (IAP-1) and reduced bax levels associated with the anti-flt-1-induced increase of intimal SMC survival; the latter was prevented by NF-{kappa}B activity inhibitor and IAP-1 interfering RNA (RNAi). Blocking of NF-{kappa}B activity reduced IAP-1 expression and prevented IAP-1 RNAi effects. Increased flt-1 immunoreaction was also documented in human atheromatous lesions.

Conclusion: Our results show that anti-flt-1 blocking reduces apoptosis through NF-{kappa}B and the downstream IAP-1 pathway. The close link between flt-1, PlGF, and apoptotic susceptibility of intimal SMCs suggests new potential strategies aimed at influencing post-injury arterial remodelling.

KEYWORDS Flt-1; Apoptosis; NF-{kappa}B; IAP-1; Vascular remodelling

Time for primary review: 40 days


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