Intimal accumulation of smooth muscle cells contributes to the development and progression of atherosclerotic lesions and restenosis following endovascular procedures. Arterial smooth muscle cells display heterogeneous phenotypes in both physiological and pathological conditions. In response to injury, dedifferentiated or synthetic smooth muscle cells proliferate and migrate from the tunica media into the intima. As a consequence, smooth muscle cells in vascular lesions show a prevalent dedifferentiated phenotype compared to the contractile appearance of normal media smooth muscle cells. The discovery of abundant stem antigen-expressing cells in vascular lesions also rarely detected in the tunica media of normal adult vessels stimulated a great scientific debate concerning the possibility that proliferating vascular wall-resident stem cells accumulate into the neointima and contribute to the progression of lesions. Although several experimental studies support this hypothesis, others researchers suggest a positive effect of stem cells on plaque stabilization. So, the real contribute of vascular wall-resident stem cells to pathological vascular remodelling needs further investigation. This review will examine the evidence and the contribution of vascular wall-resident stem cells to arterial pathobiology, in order to address future investigations as potential therapeutic target to prevent the progression of vascular diseases.
Adult ; Endovascular Procedures ; Humans ; Myocytes, Smooth Muscle ; Neointima ; Pathology* ; Phenotype ; Stem Cells* ; Tunica Media ; Vascular Diseases

BACKGROUNDStent-based delivery of sirolimus has been shown to reduce neointimal hyperplasia significantly. However, the long-term effect of the polymer is thought to initiate and sustain an inflammatory response and contribute to the occurrence of late complications. Our study aimed to evaluate the efficacy and safety of the BuMA biodegradable drug-coated sirolimus-eluting stent (BSES) for inhibiting neointimal hyperplasia in a porcine coronary model.

METHODSFour types of stents were implanted at random in different coronary arteries of the same pig: BSES (n = 24), bare metal stent (BMS) (n = 24), biodegradable polymer coated stent without drug (PCS) (n = 24) and only poly (n-butyl methacrylate) base layer coated stent (EGS) (n = 23). In total, 26 animals underwent successful random placement of 95 oversized stents in the coronary arteries. Coronary angiography was performed after 28 days, 90 days and 240 days of stent implantation. After 14 days, 28 days, 90 days and 240 days, 6 animals at each timepoint were sacrificed for histomorphologic analysis.

RESULTSThe 28-day, 90-day and 240-day results of quantitative coronary angiography (QCA) showed reduction in luminal loss (LL) in the BSES group when compared with the BMS group; (0.20 ± 0.35) mm vs. (0.82 ± 0.51) mm (P = 0.035), (0.20 ± 0.30) mm vs. (0.93 ± 0.51) mm (P = 0.013), and (0.18 ± 0.16) mm vs. (0.19 ± 0.24) mm (P = 0.889), respectively. By 28-day, 90-day and 240-day histomorphomeric analysis results, there was also a corresponding significant reduction in neointimal tissue proliferation with similar injury scores of BSES compared with the BMS control; average neointimal area (0.90 ± 0.49) mm(2) vs. (2.16 ± 1.29) mm(2) (P = 0.049), (1.53 ± 0.84) mm(2) vs. (3.41 ± 1.55) mm(2) (P = 0.026), and (2.43 ± 0.95) mm(2) vs. (3.12 ± 1.16) mm(2) (P = 0.228), respectively. High magnification histomorphologic examination revealed similar inflammation scores and endothelialization scores in both the BSES and BMS groups.

CONCLUSIONSThe BuMA biodegradable drug-coated sirolimus-eluting stents can significantly reduce neointimal hyperplasia and in-stent restenosis. Re-endothelialization of the BuMA stent is as good as that of the BMS in the porcine coronary model due to the reduced inflammation response to the BuMA stent.

Absorbable Implants ; Animals ; Coronary Angiography ; Drug-Eluting Stents ; Female ; Hyperplasia ; pathology ; Neointima ; prevention & control ; Polymers ; chemistry ; Sirolimus ; therapeutic use ; Swine

PURPOSE: There is a lack of sufficient data in comparison of optical coherence tomographic (OCT) findings between first- and second-generation drug-eluting stents (DES). Compared to first-generation (i.e., sirolimus- or paclitaxel-eluting stents), second-generation DESs (i.e., everolimus- or biolinx-based zotarolimus-eluting stents) might have more favorable neointimal coverage. MATERIALS AND METHODS: Follow-up OCT findings of 103 patients (119 lesions) treated with second-generation DESs were compared with those of 139 patients (149 lesions) treated with first-generation DESs. The percentage of uncovered or malapposed struts, calculated as the ratio of uncovered or malapposed struts to total struts in all OCT cross-sections, respectively, was compared between the two groups. RESULTS: Both DES groups showed similar suppression of neointimal hyperplasia (NIH) on OCT (mean NIH cross-sectional area; second- vs. first-generation=1.1+/-0.5 versus 1.2+/-1.0 mm2, respectively, p=0.547). However, the percentage of uncovered struts of second-generation DESs was significantly smaller than that of first-generation DESs (3.8+/-4.8% vs.7.5+/-11.1%, respectively, p<0.001). The percentage of malapposed struts was also significantly smaller in second-generation DESs than in first-generation DESs (0.4+/-1.6% vs.1.4+/-3.7%, respectively, p=0.005). In addition, intra-stent thrombi were less frequently detected in second-generations DESs than in first-generation DESs (8% vs. 20%, respectively, p=0.004). CONCLUSION: This follow-up OCT study showed that second-generation DESs characteristically had greater neointimal coverage than first-generation DESs.
Aged ; Coronary Angiography ; *Drug-Eluting Stents ; Female ; Humans ; Male ; Middle Aged ; Neointima/pathology/prevention & control ; Tomography, Optical Coherence/*methods

OBJECTIVETo study the expression of cell cycle related factor sonic hedgehog (SHH) in autogenous vein graft and its relation with neointima formation.

METHODSAutogenous vein graft model were established in 24 male Wistar rats of 8 weeks old and 140 g weight, by transplanting the left jugular vein to intra renal abdominal aorta with microsurgical technique. Graft veins were harvested at 14 d and 28 d after transplantation. The immunohistochemistry and Western blot were used to detect the SHH and PCNA expression in the vein graft. At the same time SHH mRNA was measured by quantitative real-time PCR. The opposite normal veins served as control.

RESULTSHistological staining showed that the percent of SHH+ cells was only (2.0 +/- 0.5)% in the normal vein, but was much more in the vein graft after surgery, as (39.4 +/- 0.4)% and (63.0 +/- 0.3)% respectively (P < 0.01). The expression of SHH and PCNA were both elevated in the vein graft. There was a positive correlation between them which indicated by Western blot (r = 0.808, P < 0.01). The SHH mRNA content also increased in vein graft to 9.5 and 23.8 folds of that in control.

CONCLUSIONSHH is upregulated in autogenous vein grafts and may correlated with the proliferation of vascular smooth muscle cells.

Animals ; Hedgehog Proteins ; metabolism ; Male ; Neointima ; metabolism ; Rats ; Rats, Wistar ; Transplantation, Autologous ; Tunica Intima ; metabolism ; Veins ; metabolism ; pathology ; transplantation

OBJECTIVETo study the relationship between inflammation and neointimal proliferation after coronary stent implantation in porcine model.

METHODSTwenty normal minipigs were randomly divided into group A (implanted with 316L bare metal stents), group B (implanted with 605L bare metal stents), group C (implanted with PLGA coating 605L stents), and group D (implanted with rapamycin-loaded PLGA coating 605L stents). Each minipig was implanted with two same stents in left anterior descending artery and right coronary artery. Four weeks later, the animals were sacrificed and histomorphometric measurements on the stent-segment coronary arteries were made to calculate the correlation between inflammation area and neointimal area.

RESULTSGroup D had the smallest neointimal area [(0.64 +/- 0.38) mm2, P < 0. 001] and inflammation area (median 0.00 mm2, P = 0.009) among all the groups, while there were no statistical differences among group A, B, and C in neointimal area [(2.09 +/- 0.90), (2.11 +/- 1.07), and (1.42 +/- 0.35) mm2 respectively] and in inflammation area (0.22 , 0.21, and 0.09 mm2, respectively). Bivariate correlation analysis showed that the inflammation area was positively correlated with the neointimal area (P < 0.001, correlation coefficient = 0.719). When stent type, mean injury score, and EEL area were adjusted, partial correlations analysis showed that the inflammation area was still positively correlated with the neointimal area (P = 0.01, correlation coefficient = 0.498).

CONCLUSIONInflammation promotes the neointimal proliferation after coronary stent implantation. Sirolimus-eluting stent may reduce the inflammatory response.

Animals ; Coronary Vessels ; pathology ; Drug-Eluting Stents ; adverse effects ; Inflammation ; pathology ; Neointima ; pathology ; Stents ; adverse effects ; Swine ; Swine, Miniature ; Tunica Intima ; pathology

OBJECTIVETo evaluate the accuracy of optical coherence tomography (OCT) in evaluating neointimal proliferation in canine coronary artery following stenting.

METHODSIn 15 domestic dogs, a single bare-metal stent was implanted in the anterior descending or the circumflex branch of the left coronary artery. Ninety days after stenting, the dogs underwent coronary angiography and OCT, followed by quantitative histological assessment of neointimal proliferation in the target arterial segments. The parameters of OCT and the histological findings were analyzed comparatively.

RESULTSA total of 15 OCT-histology matched frames acquired at the point with the most severe stenosis in every stent, and 60 pathological sections from all the stents were analyzed. The difference of the stent area assessed by OCT was comparable to that defined histologically (5.01∓0.79 mm(2) vs 4.99∓0.81 mm(2), P>0.05). Neointimal thickness and area were smaller with OCT assessment than with histological assessment (0.19∓0.08 mm vs 0.22∓0.10 mm, and 1.52∓0.49 mm(2) vs 1.85∓0.78 mm(2), respectively, P<0.05). The lumen area was larger by OCT assessment than by histological assessment (3.50∓0.66 mm(2) vs 3.15 ∓ 0.43 mm(2), P<0.05). Close correlations were found between OCT and histological evaluations of the neointimal thickness (R(2)=0.5280.767), neointimal area (R(2)=0.5280.537) and stent area (R(2)=0.528), but the correlation was poor for lumen area (R(2)=0.5280.307). All the stents showed full endothelialization without thrombus or aneurysm in the stents.

CONCLUSIONOCT allows precise and reproducible assessment of neointimal proliferation in the coronary artery following stenting, but for measurement of the lumen area, OCT shows a poor correlation to histological evaluation.

Angioplasty, Balloon ; adverse effects ; instrumentation ; Animals ; Coronary Angiography ; Coronary Vessels ; diagnostic imaging ; pathology ; Dogs ; Male ; Models, Animal ; Neointima ; pathology ; Stents ; adverse effects ; Tomography, Optical Coherence ; Tunica Intima ; pathology

Late stent thrombosis (LST) which is a life threatening complication has emerged as a serious problem of drug-eluting stents (DES). Several studies have suggested that incomplete neointimal coverage of stent struts contributes to LST. Progressive atherosclerosis within the neointima is an another possible cause of LST, but this phenomenon has seldom been reported in DES. We present a case of LST following DES implantation after a period of 28 months due to ruptured atheromatous plaque, despite complete neointimal coverage of stent struts proven by optical coherence tomography.
*Angioplasty, Balloon, Coronary ; Coronary Angiography ; *Drug-Eluting Stents ; Humans ; Male ; Middle Aged ; Neointima/*pathology/ultrasonography ; Thrombosis/pathology/ultrasonography ; Tomography, Optical Coherence/*methods ; Ultrasonography, Interventional/*methods

OBJECTIVETo investigate the effects of human tissue kallikrein 1(Ad-hKLK1) gene delivery on the neointima formation in carotid arteries of spontaneously hypertensive rats (SHRs).

METHODSCarotid artery restenosis was induced in male SHR rats by balloon-injury. Rats were randomly assigned into 4 groups: Sham-operated (n = 6); Angioplasty (phosphate buffered solution 50 microl, n = 8); Vector virus (control virus, 1 x 10(9) IU in 50 microl, n = 8) and Ad-hKLK1(Ad-hKLK1, 1 x 10(9) IU in 50 microl, n = 8). Rats were sacrificed 4 weeks later. The wall-to-lumen area ratio and intima/media ratio in carotid artery were assessed by image analysis in HE stained sections. The mRNA bradykinin receptor (B1R and B2R) expressions were detected by RT-PCR. The protein expression of the cycle-independent kinase inhibitors p27Kip1 and p2lCip1 were determined by Western blot analysis.

RESULTSWall-to-lumen area ratio reduced 35.6% and intima/media ratio reduced 38.8%in Ad-hKLK1 treated SHRs compared to angioplasty group (all P < 0.001). The expression of p27Kip1 and p2lCip1 increased significantly in Ad-hKLK1 treated SHRs compared with angioplasty rats (all P < 0.001). The mRNA expression of B2R was significantly upregulated in angioplasty rats compared with sham-operated rats (P < 0.05) while mRNA expression of B1R was similar between the 2 groups.

CONCLUSIONhKLK1 gene delivery may effectively reduce neointimal formation via downregulating bradykinin B2R and up-regulating the expressions of p27Kip1, p2lCip1 signaling pathways in carotid arteries of SHRs after balloon injury.

Angioplasty, Balloon ; adverse effects ; Animals ; Carotid Artery, Common ; pathology ; Gene Transfer Techniques ; Humans ; Male ; Neointima ; etiology ; Rats ; Rats, Inbred SHR ; Tissue Kallikreins ; genetics

Very late stent thrombosis is a life-threatening complication of implantation of drug-eluting stent (DES). The mechanisms are still unidentified. Stent malapposition is supposed to be one debated reason. Here we report a case of 33 months after DES implanted. Observed by optical coherence tomography, we detected a lipid-rich plaque with defective fibrous cap within the neointima and many local aneurysmal dilatations between stent struts, which mimic “malapposition” on the angiogram. These indicated that vulnerable plaque hidden in the neointima at the stent segment might be a potential mechanism of very late stent thrombosis after DES implantation.
Coronary Aneurysm ; pathology ; Dilatation, Pathologic ; Drug-Eluting Stents ; adverse effects ; Humans ; Male ; Middle Aged ; Neointima ; diagnosis ; Plaque, Atherosclerotic ; diagnosis ; Tomography, Optical Coherence ; methods

BACKGROUNDEndothelial cell damage is an important pathophysiological step of restenosis after angioplasty and stenting. Cell transplantation has great therapeutic potential for endothelial recovery. We investigated the effect of transplanting endothelial progenitor cells (EPCs) derived from human early fetal aortas in rat injured arteries.

METHODSThe carotid arterial endothelium of Sprague-Dawley rats was damaged by dilatation with a 1.5 F balloon catheter, and then EPCs derived from human early fetal aortas (<14 weeks) were injected into the lumen of the injured artery in transplanted rats, with an equal volume of normal saline injected into control rats. Rats were sacrificed at 2 and 4 weeks after treatment and transplanted cells were identified by immunohistochemical staining with anti-human CD31 and anti-human mitochondria antibodies. Arterial cross-sections were analyzed by pathology, immunohistochemistry, and morphometry.

RESULTSGreen fluorescence-labeled EPCs could be seen in the endovascular surface of balloon-injured vessels after transplantation. The intimal area and intimal/medial area ratio were significantly smaller in the transplanted group than in the control (P < 0.05) and the residual lumen area was larger (P < 0.05). After EPC transplantation, a complete vascular endothelial layer was formed, which was positive for human von Willebrand factor after immunohistochemical staining, and immunohistochemical staining revealed many CD31- and mitochondria-positive cells in the re-endothelialized endothelium with EPC transplantation but not control treatment.

CONCLUSIONEPCs derived from human early fetal aorta were successfully transplanted into injured vessels and might inhibit neointimal hyperplasia after vascular injury.

Animals ; Carotid Arteries ; pathology ; Cell Adhesion ; physiology ; Cell Survival ; physiology ; Cell Transplantation ; Endothelial Progenitor Cells ; cytology ; physiology ; Humans ; Immunohistochemistry ; Microscopy, Fluorescence ; Neointima ; therapy ; Rats ; Rats, Sprague-Dawley