Thalidomide attenuates neointimal hyperplasia by regulating smooth muscle cell proliferation and apoptosis after angioplasty: evidence from an experimental rabbit model

P. Böttger (Gießen)¹, C. Huth (Mainz)², I. Julia (Giessen)³, H. Darius (Berlin)⁴, K. Werdan (Halle (Saale))⁵, S. T. Sossalla (Gießen)⁶, M. Buerke (Siegen)^7
1Universitätsklinikum Gießen und Marburg GmbH Medizinische Klinik I - Innere Medizin, Kardiologie und Angiologie Gießen, Deutschland; ²Johann Gutenberg Universität Mainz Mainz, Deutschland; ³Justus Liebig Universität Giessen Klinik für Kardiologie Giessen, Deutschland; ⁴Berlin, Deutschland; ⁵Universitätsklinikum Halle (Saale) Klinik und Poliklinik für Innere Medizin III - Forschungslabor Halle (Saale), Deutschland; ⁶Universitätsklinikum Gießen und Marburg GmbH Medizinische Klinik I - Kardiologie und Angiologie Gießen, Deutschland; ⁷St. Marien Krankenhaus Siegen gGmbH Med. Klinik II, Kardiologie, Angiologie, Intern. Intensivmed. Siegen, Deutschland

Abstract

Background: Neointimal hyperplasia following balloon angioplasty remains a major cause of restenosis. Thalidomide, an immunomodulatory and anti-angiogenic compound, may attenuate smooth muscle cell (SMC) proliferation through cereblon-mediated modulation of NF-κB and VEGF signaling. We investigated the local vascular effects of intramural thalidomide delivery in a rabbit iliac balloon injury model.

Methods: Iliac arteries of 24 New Zealand White rabbits were randomized to receive local intramural infusion of vehicle (0.9% NaCl), vehicle + dimethylformamide (DMF, 7% v/v), thalidomide (1 mg/mL in 7% DMF), or cycloheximide (0.5 mg/mL in 7% DMF) immediately after angioplasty (n = 6 per group). An undilated control cohort (n = 9) and time-course vehicle subgroups (1, 2, 3 weeks; n = 5/5/8) were included. Each compound (2 mL) was delivered locally via a perfusion-balloon catheter at 6 atm for 30 s. Histomorphometry, intima-to-media (I/M) ratio, and immunohistochemical analyses (BrdU, TUNEL) were performed at 3 weeks by blinded observers.

Results: Local thalidomide delivery reduced I/M ratio by 30 % versus DMF vehicle (p = 0.08) and tended to decrease BrdU-positive SMC proliferation without inducing significant apoptosis (TUNEL p = 0.41). DMF alone produced a mild apoptotic signal in vitro but not in vivo. Cycloheximide markedly suppressed proliferation but caused focal medial injury. No systemic toxicity was observed. In vitro, thalidomide inhibited SMC proliferation at concentrations ≤ 100 µM, while higher doses were confounded by solvent effects.

Conclusions: Local intramural thalidomide delivery during angioplasty attenuated neointimal growth without significant cytotoxicity. The moderate anti-proliferative effect and preserved vessel integrity support further evaluation of thalidomide analogues or cereblon-targeted strategies for vascular restenosis prevention.

Keywords: Thalidomide; Neointimal Hyperplasia; Restenosis; Angioplasty; Vascular Smooth Muscle Cells; Extracellular Matrix; Apoptosis; Proliferation; Cereblon; NF-κB Signaling; Immunomodulation; Local Drug Delivery; Experimental Rabbit Model