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

• Published in: American journal of physiology. Heart and circulatory physiology 2014-11, Vol.307 (10), p.H1419-H1429
• Main Authors: Gregory, Elaine K, Webb, Antonio R, Vercammen, Janet M, Flynn, Megan E, Ameer, Guillermo A, Kibbe, Melina R
• Format: Article
• Language: English
• Subjects: Adventitia - drug effects; Adventitia - metabolism; Adventitia - pathology; Animals; Apoptosis - drug effects; Carotid Artery Injuries - metabolism; Carotid Artery Injuries - pathology; Carotid Artery Injuries - therapy; Carotid Artery, Common - drug effects; Carotid Artery, Common - metabolism; Carotid Artery, Common - pathology; Carotid Stenosis - metabolism; Carotid Stenosis - pathology; Carotid Stenosis - therapy; Cell Proliferation - drug effects; Cells; Cells, Cultured; Chromatography; Citrates - chemistry; Coronary vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Carriers; Fibroblasts - drug effects; Fibroblasts - metabolism; Hyperplasia; Macrophages - drug effects; Macrophages - pathology; Male; Mass spectrometry; Membranes; Membranes, Artificial; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Neointima; Polymers - chemistry; Rats, Sprague-Dawley; Recurrence; Rodents; Time Factors; Tretinoin - administration & dosage; Vascular Biology and Microcirculation; Vascular Cell Adhesion Molecule-1 - metabolism
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00914.2013

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.