Vascular inflammation and repair: implications for re-endothelialization, restenosis, and stent thrombosis

Abstract

The cellular and molecular processes that control vascular injury responses after percutaneous coronary intervention involve a complex interplay among vascular cells and progenitor cells that control arterial remodeling, neointimal proliferation, and re-endothelialization. Drug-eluting stents (DES) improve the efficacy of percutaneous coronary intervention by modulating vascular inflammation and preventing neointimal proliferation and restenosis. Although positive effects of DES reduce inflammation and restenosis, negative effects delay re-endothelialization and impair endothelial function. Delayed re-endothelialization and impaired endothelial function are linked to stent thrombosis and adverse clinical outcomes after DES use. Compared with bare-metal stents, DES also differentially modulate mobilization, homing, and differentiation of vascular progenitor cells involved in re-endothelialization and neointimal proliferation. The effects of DES on vascular inflammation and repair directly impact clinical outcomes with these devices and dictate requirements for extended-duration dual antiplatelet therapy.

Figure 1. Transplatelet leukocyte migration

At the site of stent implantation following PCI, endothelial cells are denuded and the subendothelial matrix is exposed to flowing blood. Platelets and fibrinogen immediately adhere surface of the injured vessel. A multistep cascade of platelet and leukocyte adhesion molecules direct leukocyte adhesion to the adherent platelets in a process termed “secondary capture”. Leukocyte capture and rolling are mediated by interaction between platelet P-selectin and leukocyte PSGL-1. Arrest and firm adhesion are mediated by platelet glycoprotien Ibα and leukocyte Mac-1. Chemokines stimulate transmigration into the extraluminal tissue.

Figure 2. Differentiation of bone marrow-derived stem cells

Previously, CD34-positive cells were believed to be committed population of EPCs, however further study demonstrated that the CD34 surface antigen actually identifies undifferentiated bone marrow-derived stem cells that have the ability differentiate into EPC and SMPCs. Ischemic conditions signal differentiation toward EPC phenotypes in order to promote reendothelialization. Inflammatory conditions signal differentiation toward SMPC phenotypes that promote neointimal proliferation.

Figure 3. CD34-positive cell counts and CD34-positive cell Mac-1 expression following PCI

(A) Circulating CD34 positive cells increase following PCI. The highest levels of CD34-positve cells were seen in the peripheral blood of patients who received BMS that went on to have restenosis at 6 month angiographic follow-up. Implantation of DES was associated with a significant reduction in the number of circulating CD34 positive cells. (B) Neutrophil Mac-1 expression correlates with mobilization of CD34-positive cells. Forty eight hours after PCI, neutrophils were harvested from the coronary sinus of patients who had coronary stents implanted. Neutrophil Mac-1 expression was quantified by flow cytometry. Neutrophil Mac-1 expression at 48 hours correlated with circulating levels of CD34-positive cells 7 days after PCI, demonstrating that higher levels of local vascular inflammation are associated with increased systemic CD34-postive progenitor cell mobilization. Data are expressed as percent change of the baseline values. (adapted with permission: Inoue T, Circulation. 2007;115(5):553-561).

Figure 4. Differentiation of patient-derived CD34-positve stem cells into endothelial-like and smooth muscle-like cells following PCI

Circulating CD34-positve stem cells were isolated from peripheral blood of patients 7 days after implantation of BMS or SES. Immunohistochemical staining for CD31(A–D). (A) BMS without restenosis, (B) BMS with restenosis, (C) SES, (D) quantification of CD31-positive cell clusters. Patients that received BMS had similar differentiation of CD34-positve stem cells into CD31-positive endothelial-like cells regardless of whether they went on to have restenosis at 6 month angiographic follow-up. Patients that received SES had a significant reduction in the differentiation of CD34-positve stem cells into CD31-positive endothelial-like cells compared to patients that received BMS. Actin staining (E–H). (E) BMS without restenosis, (F) BMS with restenosis, (G) SES, (H) quantification of actin positive cells. Patients that received BMS and went on to have restenosis at 6 month angiographic follow-up had increased numbers of CD34-positve stem cells that differentiated into actin-positive smooth muscle-like cells. Patients that received SES had a significant reduction in the differentiation of CD34-positve stem cells into actin-positive smooth muscle-like cells compared to patients that received BMS. Arrow denotes representative actin-positive cell. (adapted with permission: Inoue T, Circulation. 2007;115(5):553-561).