Abstract 3696: MyD88-Dependent Pathway Initiates Neointimal Hyperplasia Development Independently of TLR4
Detection of danger signals through toll-like receptors (TLRs) has been identified as an important activation pathway of the innate immune system. We propose that the early recognition of arterial injury and the resulting induction of pro-inflammatory cytokines (which subsequently drive occlusive adaptations) are mediated by TLR-dependent pathways. Specifically, we hypothesize that TLR4 danger signaling, acting through the MyD88 adaptor protein, is a critical pathway in intimal hyperplasia (IH) development. TLR4 −/− (C3H/HeJ), MyD88 −/−, and background matched wild type control mice (C3H/HeOUJ and C57BL/6) underwent unilateral common carotid ligation. The resultant low oscillatory shear results in IH proximal to the ligature. 28 days post ligation the carotids were perfusion fixed with formalin. Morphometric analyses were performed. MyD88 mutant mice displayed significant reduction in IH as compared to wild types, as evidenced by decreased intimal area (p=0.025; n=22) and decreased intimal thickness (p=0.029). In contrast, both TLR4 mutant and wild type mice (n=14) had marked IH development, with statistically similar intimal area and intimal thickness. The innate immune response mediated by the MyD88-dependent pathway is a significant early initiator of hemodynamically induced IH. These data suggest that this MyD88-dependent pathway is activated independently of TLR4. Ongoing research on the mechanism of MyD88 mediated intimal hyperplasia offers a potential strategy for abrogating the fibroproliferative response to vascular injury.