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Apoptosis of endothelial cells triggers a caspase‐dependent anti‐apoptotic paracrine loop active on vascular smooth muscle cells
Author(s) -
Raymond MarcAndré,
Désormeaux Anik,
Laplante Patrick,
Vigneault Normand,
Filep Janos G.,
Landry Karine,
Pshezhetsky Alexey V.,
Hébert MarieJosée
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0573fje
Subject(s) - apoptosis , microbiology and biotechnology , perlecan , paracrine signalling , vascular smooth muscle , chemistry , mapk/erk pathway , caspase , autocrine signalling , biology , phosphorylation , programmed cell death , biochemistry , proteoglycan , endocrinology , extracellular matrix , receptor , smooth muscle
Increased endothelial apoptosis and decreased apoptosis of vascular smooth muscle cells (VSMC) are central to initiation of myo‐intimal thickening. We hypothesized that apoptosis of endothelial cells (EC) induces the release of anti‐apoptotic mediator(s) active on VSMC. We found that serum‐free medium conditioned by apoptotic EC decreases apoptosis of VSMC compared with fresh serum‐free medium. Inhibition of endothelial apoptosis during conditioning with a pan‐caspase inhibitor ZVAD‐FMK blocked the release of the anti‐apoptotic factor(s) active on VSMC. VSMC exposed to serum‐free medium conditioned by apoptotic EC showed increased ERK 1/2 phosphorylation, enhanced Bcl‐xl expression, and inhibition of p53 expression. Fractionation of the conditioned medium followed by mass spectral analysis identified one bioactive component as a C‐terminal fragment of the domain V of perlecan. Serum‐free medium supplemented with either a synthetic peptide containing the EGF motif of the domain V of perlecan or chondroitin 4‐sulfate, a glycosaminoglycan anchored on the domain V of perlecan, increased ERK 1/2 phosphorylation and Bcl‐xl protein levels while inhibiting apoptosis of VSMC. These results suggest that a proteolytic activity developing downstream of activated caspases in apoptotic EC initiates degradation of pericellular proteoglycans and liberation of bioactive fragments with a robust impact on inhibition of VSMC apoptosis.