Mechanism of luminal enlargement in PTCA and restenosis: a histopathological study of necropsied coronary arteries collected from various centers in Japan

Necropsy studies of coronary arteries were made in 14 patients who died after percutaneous transluminal coronary angioplasty (PTCA). Eight patients died shortly after PTCA, while the other six patients died some considerable time later. A total of 9,920 serial step sections of necropsied coronary arteries at the site of PTCA were prepared and examined histopathologically by light microscope to determine the mechanism of luminal enlargement in PTCA, as well as the occurrence of restenosis. Of the eight patients who died shortly after PTCA, two had disruption of the intima and the media in the arterial wall located opposite the site that had atheroma, in spite of the fact that the former wall is more normal than the latter. Dissection of the media was camed out in four patients and intimal desquamation performed in six. All the patients revealed fresh thrombus formation. Of the six patients who survived for a long time after PTCA was performed, two had disruption of the intima and the media located opposite the site with atheroma. In one, the media was dissected and in another, intimal desquamation was camed out. In one patient, release of atheroma into the lumen was suspected. Proliferation of intimal cells was revealed in three patients indicating that restenosis had occurred. No compression of the atheroma was observed in any of the 14 patients. The above findings led to the conclusion that the mechanisms of luminal enlargement in PTCA are: 1) intimal and medial disruption in the arterial wall located opposite the atheroma; 2) medial dissection; 3) intimal desquamation; 4) release of atheroma into the lumen; and 5) any combination of 1) -4).     

Morphology of the coronary arteries after combined thrombolysis and percutaneous transluminal coronary angioplasty for acute myocardial infarction

Autopsy findings are reported for 6 patients who died early (8, 9, 12, 13 and 14 days) or late (52 days) after combined thrombolysis and percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction. Morphologic changes in the coronary arteries at the site of revascularization included injury to the inner portion of the arterial wall (intimal splitting, subintimal dissection, medial tears and submedial dissection) and necrosis of medial smooth muscle cells. Residual mural thrombi and thrombotic reocclusion were noted within the arterial lumen. There was a beginning neointima formation in all patients who died early and a reobstructing neointima proliferation in the patient who died late after PTCA. The results of this study support the suggestion that both rupture and dissection of the inner arterial wall and necrosis of the tunica media resulting from irreversible dilatation of the grossly intact outer layers are the most important mechanisms of PTCA. Response to arterial wall injury after PTCA is a neointima formation leading to covering of mural thrombi and thrombogenic intimal, medial and adventitial substances and smoothing of the luminal surface. Large residual mural thrombi and excessive neointimal proliferation may cause restenosis within a few weeks.     

Intimal proliferation of smooth muscle cells as an explanation for recurrent coronary artery stenosis after percutaneous transluminal coronary angioplasty

The pathologic changes in the coronary arteries of three patients who died 5, 17 and 62 days, respectively, after percutaneous transluminal coronary angioplasty were studied. Changes in the vessel wall seen early after angioplasty included focal denudation of the endothelium, splits in the intima extending to and along the inner aspect of the media, focal intimal necrosis and adventitial hemorrhage. Extensive medial dissections were seen in the coronary arteries of the two patients who died 5 and 17 days after coronary angioplasty. Fibrin was deposited on the surface of the intima, within intimal cracks and in areas of intimal and medial necrosis. Focal proliferation of smooth muscle cells was prominent on neointimal surfaces of the coronary artery from the patient who died 17 days after angioplasty. The previously dilated coronary segment from the patient who died 62 days after angioplasty was stenosed by an extensive recent proliferation of smooth muscle cells that were distributed over the entire circumference of the intimal surface as well as within gaps in the old atherosclerotic plaques. This type of intimal proliferation would appear to be responsible for the recurrent coronary artery stenosis that develops in some patients after coronary angioplasty.     

Intimal thickening of human femoral arteries with special regard to elastin, Part 1. Diffuse intimal thickening due to growth and age

In infants, human femoral arteries display seam-like internal elastic lamina (IEL) covered with endothelium on the luminal side and with smooth muscle cells (SMC) on the medial side. At birth the growth of IEL is finished, correlated with a loss of microfibrils (MF) at the periphery. With the onset of the postnatal vessel growth the joints of IEL seem to be mechanically widened until they have the appearance of gaps with progressing age. After the age of 40 years there are often rod-like crystallites in the IEL, probably composed of cholesterol esters. A small first consecutive lamina (CL) can be seen already in childhood; it enlarges until the 3rd decade of life and is interpreted as a substitute to the "fragmented" IEL. After the 5th decade of life the first CL is arranged within the intima at a certain distance from the IEL and consisting of loosely arranged elastic fibrils. In very old arteries (beyond the 8th decade of life) gaps are rarely seen in the first CL. In individuals over the age of 30 years, the space between IEL and the first CL is occupied by smooth muscle cells (SMC) which are tightly packed. Additional CLs above the first CL can be found in elderly individuals, there CL obviously contribute to the intimal thickening. The ultrastructure of the elastic elements of the vessel wall and their possible function are discussed.     

Time course of smooth muscle cell proliferation in the intima and media of arteries following experimental angioplasty.

Smooth muscle cell (SMC) proliferation is known to be an important factor for the development of restenosis after percutaneous transluminal coronary angioplasty. To determine the time course of intimal and medial SMC proliferation and morphological changes after experimental angioplasty, an intimal atheroma was produced with repeated weak electrical stimulations in the right carotid artery of 45 male New Zealand White rabbits. Angioplasty was subsequently performed in 35 rabbits, and the proliferative responses were analyzed with histomorphological and immunohistological criteria at 3, 7, 14, 21, 28, and 42 days after intervention. A hemodynamic relevant stenosis after angioplasty was found in eight (23%) of 35 dilated arteries. In five rabbits the stenosis was due to a mural thrombus, and in three animals restenosis was caused by intimal SMC proliferation. In all dilated arteries the intimal wall thickness increased from 13 +/- 5 intimal cell layers (after electrical stimulation) to 33 +/- 14 cell layers during 28 days after angioplasty (p less than 0.05). Later than 4 weeks after angioplasty, no additional increase of intimal thickening occurred. Application of bromodeoxyuridine 18 and 12 hours before excision of the vessels allowed determination of the percent of cells undergoing DNA synthesis in the intima and media using monoclonal antibody against bromodeoxyuridine. SMCs were identified by alpha-actin staining. Immunohistological quantification of intimal SMC proliferation showed a maximum of cells undergoing DNA synthesis within the first 7 days after angioplasty (p less than 0.01). In contrast, medial proliferation of SMCs was delayed and showed a small but significant increase 21 days after dilatation (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

The internal elastic lamina in normal and abnormal human arteries. A barrier to the diffusion of macromolecules from the lumen

The distribution of albumin in the walls of normal and abnormal human arteries from surgical and autopsy material was studied to gain insight into the barriers affecting the outward diffusion of plasma macromolecules. In normal arteries there was a steep reduction in albumin concentration at the position of the internal elastic lamina (IEL), suggesting that it acts as a barrier to diffusion. In abnormal arteries such as small vessels present in inflammatory tissue, the IEL was frequently discontinuous and associated with intimal thickening. In these small vessels reduplication of the IEL at the luminal margin of the thickened intima appeared to offer an effective new barrier to the diffusion of albumin from the lumen. In larger vessels such as the coronary arteries of adults, which invariably showed discontinuities of the IEL and intimal thickening, no such effective reduplicated IEL was present, and albumin diffused freely into the thickened intima. These observations suggest that the failure to form and maintain an IEL surrounding the arterial lumen may be associated with continued proliferation of intimal cells and progressive intimal thickening.     

Balloon dilatation of symptomatic subacute intimal dissection presenting as restenosis

Repeat percutaneous transluminal coronary angioplasty (PTCA) for subacute intimal dissections that produce symptoms after a period of 1 month or more is reluctantly performed for fear of extension and abrupt closure. Patients were identified with demonstrated intimal dissections (intimal contrast staining or frank intimal flap) at the time of initial PTCA who returned a mean of 17.5 weeks (range 9 to 50) later with recurrent chest pain. Repeat angiography revealed luminal compromise due to dissection rather than restenosis in 22 patients. Of these, 17 underwent repeat PTCA. Elective bypass surgery without attempted PTCA was chosen in the other 5 patients because of extensive intimal dissections (greater than 2 balloon lengths) or involvement of critical branches. In the group of 17 patients who had repeat PTCA, 10 (group 1) had a frank intimal flap without persistent contrast staining after the initial PTCA, while 7 (group 2) had both persistent staining and a flap. Successful PTCA was performed in 13 of these 17 patients (76%). There were 2 abrupt closures and 2 unsatisfactory luminal openings. One of these patients required urgent coronary bypass surgery. All 10 group 1 patients had successful repeat procedures versus only 3 of 7 group 2 patients (p = 0.01). The 3 patients with the greatest degree of luminal compromise immediately after the initial PTCA had failed repeat PTCA attempts. These results suggest that repeat PTCA for subacute intimal dissections presenting as restenosis can be successfully performed in selected patients, and that the presence of contrast staining and the degree of luminal compromise by the dissection may be predictive of outcome.     

Morphological changes and smooth muscle cell proliferation after experimental excimer laser treatment

BACKGROUND. Little is known about the mechanism(s) in the development of restenosis after excimer laser angioplasty. Thus, the rationale of this study was to determine the time course of intimal and medial smooth muscle cell (SMC) proliferation and histomorphological changes after experimental excimer laser treatment. METHODS AND RESULTS. Laser ablation was performed in the right carotid artery of 34 New Zealand White rabbits after development of a fibromuscular plaque by repeated weak electrical stimulations. The vessels were excised 3, 7, 14, 21, 28, and 42 days after excimer laser treatment. Staining of alpha-actin was used to identify SMCs. In five rabbits (15%), a stenosis of more than 50% of luminal area was due to intimal proliferation of SMCs, and in four other rabbits, a total occlusion was due to organized thrombi. After the initial ablation of the performed plaque (13 +/- 6 intimal SMC layers) a continuous increase of intimal wall thickness was found from 7 +/- 6 SMC layers at 7 days to 28 +/- 5 intimal SMC layers at 28 days after excimer laser ablation (p less than 0.01). After 42 days, no additional increase of intimal thickening occurred. After bromodeoxyuridine labeling, the extent of cell proliferation (percent of cells undergoing DNA synthesis) in the intima and media was determined using a monoclonal antibody against bromodeoxyuridine. Immunohistological quantification of SMC proliferation in the intima revealed a significant increase of cells undergoing DNA synthesis at 3 (p less than 0.05) and 14 (p less than 0.01) days after laser treatment. Medial proliferation of SMCs was delayed and had a significant increase 7 days (p less than 0.05) after intervention. Twenty-one days after laser treatment, SMC proliferation in the intima as well as in the media was normalized. CONCLUSIONS. The proliferative response of SMCs after experimental excimer laser treatment will occur as a dynamic process with a maximum of SMCs undergoing DNA synthesis during 14 days after laser ablation, resulting in an increase of intimal thickening within 4 weeks after laser treatment. The extent of intimal hyperplasia due to SMC proliferation after excimer laser treatment is comparable with the effect of transluminal balloon angioplasty in this experimental model.     

Transluminal excimer laser angioplasty of experimentally-induced atheromatous plaque: morphologic changes and importance of proliferation of smooth muscle cells

To determine the time-course of morphological changes after excimer laser treatment of atherosclerotic carotid arteries, laser angioplasty was performed in 34 rabbits after production of an intimal plaque (13 +/- 6 cell layers, 30 +/- 9% stenosis) using electrical stimulations. The animals were sacrificed 3, 7, 14, 21, 28, and 42 days after laser treatment. A total or subtotal thrombotic occlusion was found in four cases. No perforation was observed, but in 10 animals histological examination evidenced a partial ablation of the medial layer with signs of local thrombus formation and local reduction of SMC in the media. In five animals a stenosis of more than 50% of luminal reduction was due to intimal proliferation of smooth muscle cells (SMC), as determined by a monoclonal antibody against alpha-actin. After the initial ablation, a continuous increase of intimal cell layers was found, from 7 +/- 6 cell layers (19 +/- 9% stenosis) at 7 days, to 28 +/- 5 cell layers (45 +/- 18% stenosis) at 28 days following excimer laser angioplasty (p less than 0.01). After 42 days no additional increase of intimal thickening occurred. Our data suggest that incidence and morphology is comparable to the proliferative response of SMC following conventional balloon angioplasty.     

反义治疗抑制再狭窄

血管再狭窄是心血管治疗领域的热点及难点，发生机制包括血管弹性回缩、血栓形成、血管重构和内膜增生。平滑肌细胞增殖、迁移在其病理形成中起关键作用。靶基因的硫代磷酸化寡核苷酸通过杂交依赖反义、G-quartet aptameric、非G—quartet apteric和非序列特异性抑制平滑肌细胞增殖、迁移及活体血管新生内膜形成。此外，硫代磷酸化寡核苷酸具有免疫调节作用。目前反义治疗多采用局部给药法进行抗再狭窄治疗。新的反义治疗抑制再狭窄策略是采用E2F诱骗寡核苷酸调节平滑肌细胞周期调节基因的表达，达到抑制平滑肌细胞增殖的目的。     

转化生长因子-beta1与冠状动脉内膜增厚及平滑肌细胞增生的关系

目的通过检测扩张性心肌病(DCM)的冠状动脉组织,研究转化生长因子-beta1(TGF-β1)与冠状动脉的内膜增厚的联系。方法解剖20例DCM心脏移植术的受体心脏的冠状动脉,检测冠状动脉壁的中层和内膜层组织的α平滑肌肌动蛋白(α-SMA)和TGF-β1的蛋白表达水平。结果组织形态观察DCM的冠脉均存在不同程度的内膜层增厚,通过免疫组化染色中对α-SMA阳性区域的分析,发现SMC广泛均一地分布在DCM冠脉壁增厚的内膜中。TGF-β1的表达与α-SMA的表达(r=0.498,P<0.05)及内膜/中层面积比(r=0.465,P<0.05)成正相关,且TGF-β1与内膜中α-SMA阳性区域的面积百分比(r=0.615,P<0.01)也成正相关。结论正常冠状动脉壁中TGF-β1的表达与冠状动脉内膜增厚及SMC在内膜中的增生成正相关。     

Production of platelet-derived growth factor-like molecules by cultured arterial smooth muscle cells accompanies proliferation after arterial injury.

The migration and proliferation of smooth muscle cells (SMCs) within the intima of arteries following mechanical injury is thought to be initiated by vessel wall injury and release of growth factors, in particular the platelet-derived growth factor (PDGF). However, the mechanism by which SMC proliferation is regulated after platelet interaction with the vessel wall has ceased is unknown. Here we show that SMCs derived from the intima of injured rat arteries (intimal SMCs) are phenotypically distinct from SMCs from unmanipulated vessels (medial SMCs). Intimal SMCs secrete 5-fold greater amounts of PDGF-like activity into conditioned medium in culture, have fewer receptors for 125I-labeled PDGF, and are not mitogenically stimulated by exogenous purified PDGF. This study demonstrates that two SMC phenotypes can develop in the adult rat artery and suggests that SMC proliferation in vivo may be controlled, in part, by SMCs that produce PDGF-like molecules.     

The evolution of early fibromuscular lesions hemodynamically induced in the dog renal artery. I. Light and transmission electron microscopy.

In view of the important roles of arterial intimal fibromuscular lesions as precursors of atherosclerotic plaque and occlusive lesions in arterial reconstructions, a model has been developed for the rapid hemodynamic induction of these lesions by anastomosis of the dog right renal artery to the inferior vena cava. Light and transmission electron microscopic observations were made on the arterial shunt after periods of rapid flow ranging form 10 minutes to 2 hours to identify initial factor(s) and evolutionary mechanisms in the etiology of the lesions. The sequence of events included aberrations in ruthenium red staining of the endothelial luminal membrane at 10 minutes, multilayered thickening of the subendothelial basement membrane (BM) at 15 minutes, and initial reorientation and migration of smooth muscle cells (SMC) into the intima along with the appearance of areas of degeneration of the internal elastic lamina (IEL) at 30 minutes. The endothelial cells were still intact in some areas overlying the SMC migration and IEL degeneration, but they were separating from the surface in other such areas. As subendothelium became exposed, some platelet adherence was noted. By 2 hours, the entire wall reaction was fully developed. Initial observations indicate that in the evolution of this hemodynamically induced lesion visible alteration in the endothelial cells is not prerequisite to degeneration of the underlying IEL and reorientation and migration of medial SMC.     

Adaptive remodeling of internal elastic lamina and endothelial lining during flow-induced arterial enlargement.

Gaps in the internal elastic lamina (IEL) have been observed in arteries exposed to high blood flow. To characterize the nature and consequences of this change, blood flow was increased in the carotid arteries of 56 adult, male, Japanese white rabbits by creating an arteriovenous fistula between the common carotid artery and the external jugular vein. The common carotid artery proximal to the arteriovenous fistula was studied at intervals from 1 hour to 8 weeks after exposure to high flow. In the controls, the IEL showed only the usual, small, physiological holes, 2 to 10 microm in diameter. At 3 days, some of the holes in the IEL had become enlarged, but they could not be detected by scanning electron microscopy, despite manifest endothelial cell proliferation. At 4 days, gaps in the IEL appeared as small, luminal surface depressions, 15 to 50 microm wide. At 7 days, the gaps in the IEL had enlarged and formed circumferential, luminal depressions occupying 15+/-5% of the lumen surface. Endothelial cell proliferation persisted in the gaps while proliferative activity decreased where the IEL remained intact. At 4 weeks, as the artery became elongated and dilated, the gaps in the IEL widened as intercommunicating circumferential and longitudinal luminal depressions occupying 64+/-5% of the lumen surface. At 8 weeks, the rate of elongation and dilatation of the artery slowed and the widening of the gaps in the IEL diminished. Endothelial cells covered the gaps throughout. We conclude that flow-induced arterial dilatation is accompanied by an adaptive remodeling of the intima. The gaps in the IEL permit an increase in lumen surface area while endothelial cell proliferation assures a continuous cell lining throughout.     

Relationship between myocardial infarction and preinfarction angina: a histopathological study of coronary arteries in two sudden death cases employing serial section

Two patients who had previously experienced old myocardial infarction and who died suddenly after an attack of chest pain were examined and discussed. In both cases two of the three main coronary arteries showed severe stenosis with canalization. Ruptured atheromatous plaque was found in the unblocked coronary artery. Fibrin was already formed and surrounded the fractured intimal collagen fiber, foam cells, and cholesterin clefts, but a luminal thrombi had not yet been formed. Fresh occluding thrombi were formed at the site of the ruptured atheromatous plaque. Coronary thrombi containing abscess components such as foam cells, cholesterin clefts, and the fractured intimal collagen fiber were found in our preliminary study. These views support the supposition that this fracture between the lumen and the plaque might precede and be responsible for the formation of the thrombus and the onset of acute myocardial infarction. It was confirmed that the attack of preinfarction angina occurred at the time of the rupture of the atheromatous plaque. The rupture of the atheromatous plaque plays an important part as an initiating factor of peinfarction angina and myocardial infarction. Thus, it is necessary to examine coronary arteries by serial histopathological section method.     

Changes of coronary artery morphology and distribution of smooth muscle cells during progression of coronary atherosclerosis after heart transplantation

To examine the changes in coronary artery morphology and the distribution of smooth muscle cells during the progression of coronary atherosclerosis after cardiac transplantation, intimal and medial tissues were evaluated and the density of smooth muscle cells in the media were measured 30 and 60 days after transplantation by microspectrophotometry from rats receiving both auto- and allo-transplantation. Transplanted animals were given cyclosporine A to prevent graft rejection. Signs of rejection were not seen in the animals receiving auto-transplants. Rejection gradually progressed after transplantation in animals receiving allografts. The intima of the coronary arteries in the allograft group was significantly thickened at both 30 and 60 days after transplantation. The total intimal area in the day 60 group was significantly increased relative to the day 30 group among animals receiving allo-transplantation. The medial area of the coronary arteries in the group receiving allotransplantation was significantly less than that of the auto-transplantation group at both 30 and 60 days after transplantation. Azocarmine G stain revealed that the principal component of the thickened intima was smooth muscle cells. Coronary arteries in the allotransplantation group had disruption of the internal elastic lamina. We therefore hypothesized that the smooth muscle cells (SMCs) in the intima are probably derived from the media. The density of SMCs in the media was measured by microspectrophotometry. The density of SMCs was significantly decreased in the allo-transplantation group relative to the autotransplantation group. We conclude that intimal thickening of the coronary arteries is due to SMC proliferation, the myocytes being from the media through disruption of the internal elastic lamina. This process is similar to the mechanism of the development of atherosclerosis.     

Surface Profile of the Internal Elastic Lamina May Modulate Thrombosis Following Intracoronary Radiation in Balloon-Injured Porcine Arteries

Background: Intracoronary radiation (IR) can prevent neointima formation (NF) by reducing smooth muscle cell (SMC) proliferation after balloon angioplasty, but is complicated by subacute and late thrombosis. Rupture or abnormalities of the internal elastic lamina (IEL) structure and subsequent exposure of blood to the injured arterial wall can induce thrombosis and inflammation. The purpose of this study was to evaluate the effect of IR on the media and IEL after balloon overstretch injury in porcine coronary arteries. Methods: Seventeen juvenile swine (25 coronary arteries) were injured by overstretch balloon and subsequently given IR at doses of 0 or 18 Gy ⁹⁰Y prescribed to 1.2 mm from vessel wall inner surface. Two weeks following treatment, tissue sections were perfusion fixed and stained by hematoxylin-eosin or by Verhoeff-von Giesson. Smooth muscle cell α-actin was detected immunocytochemically and quantified by digital image analysis using arbitrary density units. Histomorphometry was carried out to assess intimal area (IA) and IA corrected for medial fracture length (IA/FL). The roughness index (RI) of the IEL was calculated from the surface profile length and the straight-line length. Results: NF was markedly smaller after IR as compared to control treatment. Mural thrombi were increased significantly in irradiated versus control arteries (11/14 [78%] vs 1/11 [9%]; P < 0.001). A significant decrease in SMC density was observed in the irradiated group (128 ± 13 vs 74 ± 10; P < 0.001) despite a lack of difference in medial area. The surface of the IEL was more irregular in irradiated arteries, particularly at the medial breaks (RI =20.1 ± 3.1 vs 8.7 ± 1.2; P < 0.001). When mural thrombi were present, thrombus area correlated with RI (α= 0.76; P < 0.01). Furthermore, in the irradiated group RI correlated positively with SMC density (α=0.64; P < 0.01). Conclusion: Medial structure and RI may be useful parameters by which to assess arterial healing following IR. These findings may influence the design of future IR studies aimed at reducing thrombosis and enhancing arterial healing.     

Pathological features of coronary arteries in children with Kawasaki disease in which coronary arterial aneurysm was absent at autopsy. Quantitative analysis

Coronary arteries in six children who had Kawasaki disease but lacked coronary arterial aneurysms were examined. Four children died of myocarditis at the acute stage, and two children died of bacterial sepsis or as a result of an occurrence during cineangiography at the healed stage. Twenty-one children without Kawasaki disease were examined as controls. The six children with Kawasaki disease had no thrombi, recanalization, or stenosis greater than 50% in the major coronary arteries. Three patients had dilatation of the major coronary arteries at the acute stage. Two of the three patients died during the acute stage, and autopsy showed slight dilatation of coronary arteries and abnormal intimal thickening due to panvasculitis. In the third child, who died at the healed stage, dilatation of the coronary arteries detected by two-dimensional echocardiography at the acute stage had disappeared at the healed stage. No dilatation of the major coronary arteries was seen at autopsy. However, abnormal fibrous intimal thickening of the major coronary arteries without inflammatory changes was found. The other three patients had no dilatation of the major coronary arteries at the acute stage. Two patients died at the acute stage, and slight inflammation without abnormal intimal thickening was seen in the intima and the adventitial area. In the third patient, who died during the healed stage, two-dimensional echocardiography revealed no dilatation during the clinical course, and there was no inflammatory changes or abnormal intimal thickening at autopsy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pathophysiological mechanisms for restenosis following coronary angioplasty: possible preventive alternatives

Abstract. Restenosis after successful percutaneous transluminal coronary angioplasty (PTCA) remains an unsolved medical problem. The search for the underlying pathophysiological mechanisms have identified intimal proliferation of smooth muscle cells (SMC) to be the prevailing cause of late restenosis, with endothelial cells (EC) and platelets being important participators in the process. According to the most accepted present theory, SMC would be stimulated to migrate and proliferate shortly after the angioplasty by the release of growth factors from injured EC and accumulated platelets. However, clinical trials of agents interfering with these mechanisms have not significantly diminished the rate of restenosis, which suggest both that our knowledge of the process is incomplete, and that new ways of administrating the agents may be required.     

Lack of inhibition of DNA synthesis by prostaglandin I2 in cultured intimal smooth muscle cells from rabbits

The negative control system for proliferation by prostaglandin I2 (PGI2) was studied in the smooth muscle cells (SMC) cultured from the thickened intima (intimal SMC) of rabbit aortas. Indomethacin was found to enhance DNA synthesis of medial SMC but not that of intimal SMC. Exogenously added PGI2 or its stable analogue, CS-570, was observed to inhibit DNA synthesis of medial SMC enhanced by indomethacin but not that of intimal SMC. These results indicate that medial SMC are negatively controlled by endogenous PGI2 and that intimal SMC have no such negative control system for cell proliferation. This lack of negative control may be one of the mechanisms underlying the rapid growth behavior of intimal SMC as compared to medial SMC.