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Cardiovascular Research 2006 72(2):339-348; doi:10.1016/j.cardiores.2006.07.017
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Copyright © 2006, European Society of Cardiology

Hyaluronan induces vascular smooth muscle cell migration through RHAMM-mediated PI3K-dependent Rac activation

Yann Gouëffica,b,*, Christophe Guilluya, Patrice Guérina,b, Philippe Patrab, Pierre Pacauda and Gervaise Loiranda,b,*

aInserm, Université de Nantes, U533, l'institut du thorax, Nantes, F-44000, France
bCentre Hospitalier Universitaire de Nantes, Nantes, F-44000, France

* Corresponding authors. Inserm U-533, Université de Nantes, L'institut du Thorax, Faculté des Sciences, 2 rue de la Houssinière, BP 92208, Nantes F-44000, France. Email address: yann.goueffic{at}chu-nantes.fr gervaise.loirand{at}univ-nantes.fr

Objective: Hyaluronan (HA) is an important constituent of the extracellular matrix and is known to regulate cellular events through binding to CD44 and the receptor for HA-mediated motility (RHAMM). Here we investigated the role of these receptors and the signaling pathways involved in HA-mediated effects in arterial smooth muscle cells (ASMC).

Methods: Effects of high-molecular weight HA (1 to 5 mg/ml) were analyzed in cultured ASMC from rat aorta.

Results: HA promoted actin stress fiber and lamellipodia formation and dose-dependently induced ASMC migration without effect on proliferation. Pull-down assay of Rho protein activity indicated that HA activated RhoA and Rac. HA-induced ASMC migration was not affected by the RhoA inhibitor Tat-C3 (10 µg/ml), the Rho kinase inhibitor Y-27632 (10 µM) and blocking anti-CD44 antibody, but was reduced by the non-selective Rho protein inhibitor simvastatin (10 µM), the Rac inhibitor LT-toxin (1 µg/ml), small interfering RNA (siRNA) targeting Rac and the phosphatidyl inositol 3-kinase (PI3K) inhibitor LY294002 (25 µM), which also blocked HA-induced Rac activation. CD44 knockdown by siRNA inhibited HA-mediated RhoA activation without effect on ASMC migration. In contrast, siRNA targeting RHAMM inhibited both HA-induced migration and Rac activation.

Conclusions: High-molecular weight HA independently activates RhoA and Rac through CD44 and RHAMM, respectively. HA-induced migration depends exclusively on RHAMM-mediated PI3K-dependent Rac activation.

KEYWORDS Smooth muscle; Extracellular matrix; Signal transduction; Receptors; G-proteins

Time for primary review 19 days


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