Vascular smooth muscle cell proliferation depends on caveolin-1-regulated polyamine uptake.

Mario Grossi,Bengt-Olof Nilsson,Karl Swärd,David Erlinge,Catarina Rippe,Lo Persson,Amalia Forte,Per Hellstrand,Ramasri Sathanoori

doi:10.1042/bsr20140140

Mario Grossi, Bengt-Olof Nilsson + Show 7 more

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https://doi.org/10.1042/bsr20140140

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Abstract

Much evidence highlights the importance of polyamines for VSMC (vascular smooth muscle cell) proliferation and migration. Cav-1 (caveolin-1) was recently reported to regulate polyamine uptake in intestinal epithelial cells. The aim of the present study was to assess the importance of Cav-1 for VSMC polyamine uptake and its impact on cell proliferation and migration. Cav-1 KO (knockout) mouse aortic cells showed increased polyamine uptake and elevated proliferation and migration compared with WT (wild-type) cells. Both Cav-1 KO and WT cells expressed the smooth muscle differentiation markers SM22 and calponin. Cell-cycle phase distribution analysis revealed a higher proportion of Cav-1 KO than WT cells in the S phase. Cav-1 KO cells were hyper-proliferative in the presence but not in the absence of extracellular polyamines, and, moreover, supplementation with exogenous polyamines promoted proliferation in Cav-1 KO but not in WT cells. Expression of the solute carrier transporters Slc7a1 and Slc43a1 was higher in Cav-1 KO than in WT cells. ODC (ornithine decarboxylase) protein and mRNA expression as well as ODC activity were similar in Cav-1 KO and WT cells showing unaltered synthesis of polyamines in Cav-1 KO cells. Cav-1 was reduced in migrating cells in vitro and in carotid lesions in vivo. Our data show that Cav-1 negatively regulates VSMC polyamine uptake and that the proliferative advantage of Cav-1 KO cells is critically dependent on polyamine uptake. We provide proof-of-principle for targeting Cav-1-regulated polyamine uptake as a strategy to fight unwanted VSMC proliferation as observed in restenosis.

Highlights

Restenosis of the carotid artery is common after carotid endarterectomy (CEA)
We showed recently that the local inhibition of ornithine decarboxylase (ODC), a rate-limiting enzyme in the biosynthesis of polyamines, by α-DFMO reduces vascular stenosis in a murine model of carotid injury, suggesting that DFMO can be used to prevent the unwanted proliferation of vascular smooth muscle cell (VSMC) in restenosis [17]
Cav-1 KO aortic smooth muscle cell (ASMC) show increased proliferation and migration rates compared with WT cells Cav-1 KO and WT ASMCs were seeded in FBS-containing media, naturally containing a low concentration of polyamines, to monitor cell proliferation

Summary

Introduction

Restenosis of the carotid artery is common after CEA (carotid endarterectomy). It is reported that restenosis occurs in approximately 10 % of patients within the first year following CEA, with even more patients developing restenosis in the longer term [1]. CEA is characterized by a complex interaction of proliferation and migration of smooth muscle cells and fibroblasts, extracellular matrix accumulation, and thrombus formation at the injured site, collectively causing narrowing of the blood vessel lumen. Since VSMC (vascular smooth muscle cell) proliferation is an important feature in the progression of restenosis, much effort is spent on finding ways to inhibit this process. Stents are coated with anti-cancer drugs such as the microtubule disruptor paclitaxel [2]. Owing to unwanted side-effects and therapy resistance there is a strong need for new and effective anti-proliferative drugs with low toxicity to combat restenosis

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