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Periadventitial atRA citrate-based polyester membranes reduce neointimal hyperplasia and restenosis after carotid injury in rats.

Abstract
Oral all-trans retinoic acid (atRA) has been shown to reduce the formation of neointimal hyperplasia; however, the dose required was 30 times the chemotherapeutic dose, which already has reported side effects. As neointimal formation is a localized process, new approaches to localized delivery are required. This study assessed whether atRA within a citrate-based polyester, poly(1,8 octanediolcitrate) (POC), perivascular membrane would prevent neointimal hyperplasia following arterial injury. atRA-POC membranes were prepared and characterized for atRA release via high-performance liquid chromatography with mass spectrometry detection. Rat adventitial fibroblasts (AF) and vascular smooth muscle cells (VSMC) were exposed to various concentrations of atRA; proliferation, apoptosis, and necrosis were assessed in vitro. The rat carotid artery balloon injury model was used to evaluate the impact of the atRA-POC membranes on neointimal formation, cell proliferation, apoptosis, macrophage infiltration, and vascular cell adhesion molecule 1 (VCAM-1) expression in vivo. atRA-POC membranes released 12 μg of atRA over 2 wk, with 92% of the release occurring in the first week. At 24 h, atRA (200 μmol/l) inhibited [(3)H]-thymidine incorporation into AF and VSMC by 78% and 72%, respectively (*P = 0.001), with negligible apoptosis or necrosis. Histomorphometry analysis showed that atRA-POC membranes inhibited neointimal formation after balloon injury, with a 56%, 57%, and 50% decrease in the intimal area, intima-to-media area ratio, and percent stenosis, respectively (P = 0.001). atRA-POC membranes had no appreciable effect on apoptosis or proliferation at 2 wk. Regarding biocompatibility, we found a 76% decrease in macrophage infiltration in the intima layer (P < 0.003) in animals treated with atRA-POC membranes, with a coinciding 53% reduction in VCAM-1 staining (P < 0.001). In conclusion, perivascular delivery of atRA inhibited neointimal formation and restenosis. These data suggest that atRA-POC membranes may be suitable as localized therapy to inhibit neointimal hyperplasia following open cardiovascular procedures.
AuthorsElaine K Gregory, Antonio R Webb, Janet M Vercammen, Megan E Flynn, Guillermo A Ameer, Melina R Kibbe
JournalAmerican journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 307 Issue 10 Pg. H1419-29 (Nov 15 2014) ISSN: 1522-1539 [Electronic] United States
PMID25239800 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 the American Physiological Society.
Chemical References
  • Citrates
  • Drug Carriers
  • Membranes, Artificial
  • Polymers
  • Vascular Cell Adhesion Molecule-1
  • poly(1,8-octanediol citrate)
  • Tretinoin
Topics
  • Adventitia (drug effects, metabolism, pathology)
  • Animals
  • Apoptosis (drug effects)
  • Carotid Artery Injuries (metabolism, pathology, therapy)
  • Carotid Artery, Common (drug effects, metabolism, pathology)
  • Carotid Stenosis (metabolism, pathology, therapy)
  • Cell Proliferation (drug effects)
  • Cells, Cultured
  • Citrates (chemistry)
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Carriers
  • Fibroblasts (drug effects, metabolism)
  • Hyperplasia
  • Macrophages (drug effects, pathology)
  • Male
  • Membranes, Artificial
  • Muscle, Smooth, Vascular (drug effects, metabolism)
  • Myocytes, Smooth Muscle (drug effects, metabolism)
  • Neointima
  • Polymers (chemistry)
  • Rats, Sprague-Dawley
  • Recurrence
  • Time Factors
  • Tretinoin (administration & dosage)
  • Vascular Cell Adhesion Molecule-1 (metabolism)

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