Decreased adventitial neovascularization after intracoronary irradiation in swine: a time course study

Intracoronary radiation (IR) suppresses the formation of neointima after arterial injury in swine, through mechanisms incompletely understood. Neointimal development appears related to expansion of adventitial microvessels; we therefore examined the hypothesis that IR inhibits neointima formation through an anti-angiogenic effect.

Juvenile swine were treated with either 0 or 15 Gy (192)Ir (gamma-source) and euthanized 3, 7, or 14 days later or treated with 18 Gy (90)Y (beta-source) and euthanized after 14 days. Adventitial area (AA), intimal area (IA), IA corrected for medial fracture length, and adventitial vessel area were assessed in both injured and uninjured segments by computer-aided histomorphometry on Verhoeff-Von Giesson stained sections. Adventitial vessel count (AVC) was enumerated visually on hematoxylin and eosin stained sections and confirmed by anti-factor VIII-associated antigen immunostaining for endothelial cells. AA and IA were reduced in injured arteries subjected to IR as compared to controls. The AVC was significantly lower in injured irradiated arterial segments as well as all uninjured segments as compared with injured control segments. In the injured and irradiated arteries, the AVC remained unchanged at 3, 7, and 14 days. The injured segments of arteries treated with IR demonstrated a significantly lower adventitial microvessel density (AVC/AA) as compared to the injured control segments. Comparison of gamma- and beta-irradiation at 14 days did not show any differences for vessel parameters and measurements of adventitial microvessels. IA and AVC were correlated positively (R(2) = 0.63, alpha = 0.79, p < 0.01).

IR induced an early and sustained anti-angiogenic effect between 3 and 14 days. The relation between IA and AVC may indicate an antiproliferative effect associated with an anti-angiogenic effect independent of the type of radiation.

Intracoronary radiation suppresses neointima formation after arterial injury in swine, through mechanisms and with consequences that are not fully known. Reduction of angiogenesis may inhibit restenosis. In the present study, intimal area and adventitial area were reduced in the intracoronary radiation groups 3-14 days after arterial injury as compared to their respective controls, with a parallel reduction in the adventitial vessel count and adventitial vessel density. Intimal area and adventitial vessel count were correlated positively. Neointima reduction after intracoronary radiation may depend not only on an antiproliferative effect but also on an anti-angiogenic effect.