Apoptosis-regulated survival of primarily extravascular cells in proliferative active poststent neointima

Abstract

Background: Increased proliferation, mitigated apoptosis, and recruitment of primarily extravascular cells to injured vessels are important processes during neointima formation. Therefore, the goal of this study was to assess the spatiotemporal balance between proliferation and apoptosis and the influence of apoptosis on the survival of primarily extravascular cells in in-stent neointima.

Methods: Minipigs underwent stent implantation to abdominal aortic segments. At Days 1, 7, 14, 30, 60, and 90 after injury, arterial cross sections were analyzed by TUNEL assay to detect apoptotic cells. For immunohistochemical detection of Ki67+/proliferating cell nuclear antigen (PCNA)+ proliferative, caspase3+ apoptotic, S100+/fascin+ dendritic, GFAP+ neural crest-derived cells and CD14+ monocytes/macrophages, the alkaline phosphatase-anti-alkaline phosphatase (APAAP) method was used.

Results: In the incipient cell-rich neointima, both frequency of proliferation and apoptosis was maximal (Ki67, 28.5±2.2%; PCNA, 25.4±3.8%; TUNEL, 8.6±0.4%; caspase3, 7.9±4.3%). With time, parallel to the decline in the neointima cellularity, signaling for proliferation and apoptosis decreased. Throughout the time course of neointima development, the apoptotic activity was detected in primarily extravascular cells.

Conclusions: Imbalance between proliferation and apoptosis and recruitment of dendritic cells, monocytes/macrophages, and neural crest-derived cells to the injured vessels may partly explain the formation of the hypercellular in-stent neointima. Herein, apoptosis is an important factor that regulates survival of primarily extravascular neointimal cells.