Time course of the regression of intimal hyperplasia in experimental vein grafts.

A previous study in which vein grafts were removed from the arterial circulation and reimplanted into the venous circulation of the same animal demonstrated regression of vein graft intimal hyperplasia and medial thickening within 14 days. The present study was designed to characterize the kinetics of the morphological and ultrastructural changes over this 14-day period. Twenty-one male New Zealand White rabbits received a reversed vein interposition bypass graft of the right common carotid artery. Fourteen days after the procedure, 21 vein grafts were isolated, removed, and reimplanted into the contralateral external jugular venous system as veno-venous interposition bypass grafts (reversal grafts). The grafts were harvested at 60 minutes, 1 day, 3 days, 5 days, 7 days, and 14 days after reversal. Before insertion into the venous circulation, the vein graft had a confluent endothelial cell surface with multiple layers of smooth muscle cells representing intimal hyperplasia. After 1 hour, the reversal graft retained an intact endothelial cell layer with no evidence of tissue edema or cellular disruption. By 24 hours, there were a few blood cells on the endothelial cell surface. There was no inflammatory infiltrate seen in the subendothelium, and the smooth muscle cells were unaltered. At 3 days, the endothelial cell lining remained intact with no polymorphonucleocytes in the subendothelium or within the graft wall. Underlying smooth muscle cells at this time were noted to contain cytoplasmic vacuoles. At 5 days, there were no inflammatory cells seen on the surface or within the vein graft wall, but many of the underlying smooth muscle cells within the intimal hyperplasia were noted to be fragmented and to have clumping of chromatin. After 7 days, the endothelial cells remained intact and there was widespread evidence of apoptosis beneath the subendothelium with highly fragmented smooth muscle cells, some of which were histologically in the process of breaking up. At 14 days, the grafts retained uniform endothelial cell surfaces. Most of the smooth muscle cells that composed the intimal hyperplasia seen before implantation as a reversal graft were gone. Areas of newly laid down collagen could be observed. There were no acute inflammatory cells but for some mast cells seen in the graft wall. This study demonstrates that in this model, regression of intimal hyperplasia was associated with apoptosis of the smooth muscle cells and the deposition of collagen. There was no evidence that this process is mediated by an acute inflammatory response. Regression therefore appears to be due to induction of smooth muscle cell apoptosis by either a reduction in pressure or flow or a combination of both factors. The findings will enable a systematic cellular and molecular analysis of the biology of regression, which may afford clues to better understand the biology of the developing intimal hyperplasia.     

Mouse Model of Venous Bypass Graft Arteriosclerosis

Saphenous vein grafts are widely used for treatment of severe atherosclerosis via aortocoronary bypass surgery, a procedure often complicated by later occlusion of the graft vessel. Because the molecular mechanisms of this process remain largely unknown, quantitative models of venous bypass graft arteriosclerosis in transgenic mice could be useful to study this process at the genetic level. We describe herein a new model of vein grafts in the mouse that allows us to take advantage of transgenic, knockout, or mutant animals. Autologous or isogeneic vessels of the external jugular or vena cava veins were end-to-end grafted into carotid arteries of C57BL/6J mice. Vessel wall thickening was observed as early as 1 week after surgery and progressed to 4-, 10-, 15-, and 18-fold original thickness in grafted veins at age 2, 4, 8, and 16 weeks, respectively. The lumen of grafted veins was significantly narrowed because of neointima hyperplasia. Histological and immunohistochemical analyses revealed three lesion processes: marked loss of smooth muscle cells in vein segments 1 and 2 weeks after grafting, massive infiltration of mononuclear cells (CD11b/18⁺) in the vessel wall between 2 and 4 weeks, and a significant proliferation of vascular smooth muscle cells (α-actin⁺) to constitute neointimal lesions between 4 and 16 weeks. Similar vein graft lesions were obtained when external jugular veins or vena cava were isografted into carotid arteries of C57BL/6J mice. Moreover, no significant intima hyperplasia in vein-to-vein isografts was found, although there was leukocyte infiltration in the vessel wall. Thus, this model, which reproduces many of the features of human vein graft arteriosclerosis, should prove useful for our understanding of the mechanism of vein graft disease and to evaluate the effects of drugs and gene therapy on vascular diseases.     

血小板衍生生长因子B链与血管新生促进移植物动脉血管病发展

目的以大鼠颈总动脉移植为模型探讨移植物动脉血管病（TA）的病理生理机制。方法建立大鼠颈总动脉移植模型。受体随机分3组，同系组（n=6）：Lewis至Lewis颈总动脉移植；TA组（n=7）：Brown—Norway（BN）Lewis颈总动脉移植；干预组（n=7）：BN至Lewis颈总动脉移植，术后给予阿司匹林80mg／（kg·d）治疗8周。术后8周取移植动脉做病理学分析，观察动脉内膜平滑肌细胞增殖和新生毛细血管生成情况，评估内膜增生程度；免疫组织化学法检测血小板衍生生长因子B链（PDGF-B）和环氧化酶2（COX-2）的表达。结果①同系组移植动脉内膜未见增生；TA组内膜见大量的血管平滑肌细胞（VSMC）增殖，新生内膜中见丰富的新生毛细血管形成；干预组较TA组内膜增生程度减轻（P〈0．05），内膜厚度减少48．0％。②PDGF—B、COX-2在同系组几乎不表达，而在TA组移植动脉内膜显著表达：干预组较TA组PDGF—B、COX-2表达下调，阳性细胞显著减少（P〈0．05）。结论TA的发病是一个多途径、多机制的病理生理过程：新生内膜高表达PDGF—B和血管新生促进了TA的发展。     

Immunocytochemical investigation of atherosclerotic changes observed in aortocoronary bypass vein grafts using monoclonal antibodies

The authors have performed immunocytochemical surveys on atherosclerotic changes observed in saphenous vein aortocoronary bypass grafts, comparing the changes occurring in coronary and aortic lesions. The two monoclonal antibodies used in this study were obtained by T. Tsukada. One of them, named HHF35, exhibited specificity to smooth muscle cells; the other, named HAM56, was specific to macrophages. These immunocytochemical studies clearly demonstrated that cells encountered within the fibrous intimal thickening in the vein graft were inevitably smooth muscle cell in origin. Macrophages were seldom seen in the grafts examined. In contrast to vein grafts, macrophages were noted within the intima of all specimens from arterial atherosclerotic lesions obtained from the same patients. These studies suggest a difference in the progression of intimal thickening between the venous graft and the arterial atherosclerotic lesions.     

Reduction of smooth muscle hyperplasia in vein grafts in athymic rats

While developing an animal model of a vascular malformation, we found that two doses of cyclosporin A significantly reduced the smooth muscle cell hyperplasia observed in vein-arterial interposition grafts in Sprague-Dawley rats. Therefore, we hypothesized that T cells may either produce or augment a mitogen for vascular smooth muscle cells. To further investigate this, we quantitated the extent of smooth muscle cell hyperplasia in the vein grafts of athymic nude rats that lack mature, functioning T cells. Male Sprague-Dawley rats (275 to 350 gm) and athymic nude rats were anesthetized, and a segment of the superficial epigastric vein was placed into the transected femoral artery using microsurgical techniques. Sprague-Dawley rats (N = 9) and athymic nude rats (N = 5) undergoing vein grafting received 30 mg/kg cyclosporin A intraperitoneally, intraoperatively and 24 hours later. Sprague-Dawley rats (N = 7) and athymic nude rats (N = 6) that had vein grafts were not treated with cyclosporin A. Animals were killed at either 3 weeks or 6 weeks and histologic sections were taken from the middle of the graft to avoid clamp-induced trauma. At 3 weeks, untreated vein grafts in Sprague-Dawley rats exposed to arterial pressure exhibited a nine-fold increase in smooth muscle hyperplasia compared with the preoperative vein. Treatment of Sprague-Dawley rats with cyclosporin A resulted in a 57% reduction of smooth muscle hyperplasia (p less than 0.05). Vein grafts from athymic nude rats exhibited a 51% reduction in smooth muscle hyperplasia (p less than 0.05). Sprague-Dawley rats killed at 6 weeks revealed a recovery of smooth muscle hyperplasia equivalent to an untreated Sprague-Dawley vein graft at 3 weeks. Inhibition of smooth muscle hyperplasia persisted for 6 weeks in the athymic nude rats. Cyclosporin A administration or T cell deficiency in athymic nude rats decreases the smooth muscle hyperplasia observed in venous grafts exposed to arterial pressure. This finding provides evidence for a possible role of T cells in the regulation of cell growth in the vascular wall.     

Structural features of cell death in atherosclerotic lesions affecting long-term aortocoronary saphenous vein bypass grafts

Aortocoronary saphenous vein bypass grafts fail because of structural pathologies (thrombosis, intimal hyperplasia and atherosclerosis) within the 'arterialized' vein leading to graft stenosis. This study examined structural characteristics of atherosclerotic alterations in long-term aortocoronary artery saphenous vein bypass grafts with particular attention to the features of cell death in atherosclerotic lesions. Stenotic vein grafts were obtained from 10 patients at redo coronary artery bypass grafting operations. All the grafts were affected by histological abnormalities, with eight out of ten grafts showing evidence of atherosclerotic alterations in the intimal hyperplastic layer. Areas containing foam cells were examined by electron microscopy. Cells with cytoplasmic lipid accumulations were characterized by varying degrees of chromatin condensation, fragmentation or dispersion, by focal areas of oedema and vacuolisation of their cytoplasm, and by plasmalemmal destruction. Some lipid-filled cells exhibiting signs of destruction contained myofilaments and basal membrane fragments, allowing them to be identified as smooth muscle cells. Macrophage foam cells were found to have undergone similar destruction. No cells showing nuclear degeneration were observed to have intact cytoplasmic organelles. Neither were apoptotic bodies identified, but necrotic remnants were frequently seen. The results suggest that cell death in atherosclerotic lesions affecting aortocoronary artery saphenous vein bypass grafts occurs through oncosis rather than by apoptosis.     

Nature and origin of the neointima in whole vessel wall organ culture of the human saphenous vein

Intimal proliferation is a characteristic feature of arteriosclerosis. Whole vessel wall organ culture systems have been developed to study the early stages of neointima formation. We have cultured a large number of explants of human saphenous vein specimens for several weeks, and have identified the nature of the cells in the newly formed intima by a panel of monoclonal antibodies recognizing endothelial cells (von Willebrand factor, platelet endothelial cell adhesion molecule-1 and EN-4 antigen), smooth muscle cells (monoclonal antibodies HHF35 and CGA-7) and fibroblasts (5B5 antibody). In addition we determined the uptake of fluorescently labelled acetylated low density lipoprotein by the surface cells of the explants. We found that an apparent neointima was formed in the vein organ system, the cells of which were predominantly smooth muscle cells and originated from the cut edges and from the adventitia of the vein segment. The endothelial cells originally lining the luminal surface of the vessel segments became overgrown by these cells. They remained at the base of the newly formed neointima and a number of them reorganized into capillary-like structures. Our data suggest that explant culture of saphenous vein does not reflect the classical concept of neointima formation, in which intimal smooth muscle cells migrate through the internal elastic lamina and accumulate in the intima. Although it has this limitation, the model may serve well to study specific aspects of cell migration, smooth muscle cell differentiation and angiogenesis, and may reflect aspects of intimal thickening at surgical suture sites.     

Adaptive remodelling of smooth muscle in the neo-intima of vein-to-artery grafts in rats: a detailed morphometric analysis

Summary End-to-end autogenous vein-to-artery grafts in rats have been used extensively as a model for neointimal thickening (hyperplasia), which develops over the first 6 weeks after grafting. This study employed computerised morphometric techniques to analyse 16 grafts, in order to quantitate precisely how the neointima develops. Two important features were described that have not been identified previously, due to the extensive variation in neo-intimal thickness inherent in vein grafts. Firstly, the proximal region of the graft was significantly thicker than the distal region, up until 6 months after grafting. The smooth muscle cells in the graft may have developed more rapidly in the proximal region, due to the altered haemodynamics within the graft. Secondly, within the central region of the graft the characteristic focal nature of neo-intimal hyperplasia was evident throughout the period of the study, but by 6 months the neo-intima tended to be distrubuted more evenly. By 6 months remodelling of smooth muscle throughout the graft neo-intima had occurred, and the neo-intima had matured to a thickness equivalent to that of the intima plus media of the adjacent iliac artery.     

Rapid development of vein graft atheroma in ApoE-deficient mice

Several animal models manifesting lesions resembling neointimal hyperplasia of human vein grafts have been developed, but no spontaneous atheromatous lesions in their vein grafts have been observed. We developed and here characterize a new animal model of vein graft atheroma, a maturated atherosclerotic plaque, in apoE-deficient mice. The lesion displayed classical complex morphological features and heterogeneous cellular compositions and consisted of a fibrous cap, infiltrated mononuclear cells, foam cells, cholesterol crystal structure, necrotic core with calcification, and neovasculature. Cell component analysis revealed smooth muscle cells (SMCs) localized in the cap region, macrophages which made up a large portion of the lesions, and CD4+ T cells scattered under the cap. Importantly, apoptotic/necrotic cells determined by TUNEL assay in vein grafts into apoE-/- mice were significantly higher than wild-type mice, although a similar number of proliferating cell nuclear antigen-positive cells in both types of lesions was found. Interestingly, vascular SMCs cultivated from aortas of apoE-deficient mice showed a high rate of spontaneous apoptosis/necrosis and a higher rate of cell death stimulated by a nitric oxide donor, sodium nitroprusside, H(2)O(2), and oxidized low density lipoprotein (LDL), although no difference in proliferation of both SMCs incubated with platelet-derived growth factor, angiotensin II, LDL, and oxidized LDL was seen. Thus, the pathogenic mechanisms of vein graft atheroma involve increased intimal cell death initiated by biomechanical stress and amplified by hypercholesterolemia, which leads to continuous recruitment of blood mononuclear cells to constitute atheromatous lesions. This mouse model resembling human vein graft disease has many advantages over other animal models.     

Vascular patches tissue-engineered with autologous bone marrow-derived cells and decellularized tissue matrices

Synthetic polymer vascular patches used in cardiovascular surgery have shortcomings such as thrombosis, intimal hyperplasia, calcification, infection, and no growth potential. Tissue-engineered vascular patches using autologous vascular cells may solve these problems. In this study, we developed a tissue-engineered vascular patch using autologous bone marrow-derived cells (BMCs) and decellularized tissue matrices. Vascular smooth muscle cells and endothelial cells were differentiated from bone marrow mononuclear cells in vitro. Tissue-engineered vascular patches were fabricated by seeding these cells onto decellularized canine inferior vena cava matrices and implanted into the inferior vena cava of dogs. Three weeks after implantation, the tissue-engineered vascular patches were patent with no sign of thrombus formation. Histological, immunohistochemical, and electron microscopic analyses of the vascular patches retrieved 3 weeks after implantation revealed regeneration of endothelium and smooth muscle and the presence of collagen and elastin. BMCs labeled with a fluorescent dye prior to implantation were detected in the retrieved vascular patches, indicating that the BMCs survived after implantation and contributed to the vascular tissue regeneration. This study demonstrates that vascular patches can be tissue-engineered with autologous BMCs and decellularized tissue matrices.     

Contribution of stem cells to neointimal formation of decellularized vessel grafts in a novel mouse model

Artificial vessel grafts are often used for the treatment of occluded blood vessels, but neointimal lesions commonly occur. To both elucidate and quantify which cell types contribute to the developing neointima, we established a novel mouse model of restenosis by grafting a decellularized vessel to the carotid artery. Typically, the graft developed neointimal lesions after 2 weeks, resulting in lumen closure within 4 weeks. Immunohistochemical staining revealed the presence of endothelial and smooth muscle cells, monocytes, and stem/progenitor cells at 2 weeks after implantation. Explanted cultures of neointimal tissues displayed heterogeneous outgrowth in stem cell medium. These lesional cells expressed a panel of stem/progenitor markers, including c-kit, stem cell antigen-1 (Sca-1), and CD34. Furthermore, these cells showed clonogenic and multilineage differentiation capacities. Isolated Sca-1(+) cells were able to differentiate into endothelial and smooth muscle cells in response to vascular endothelial growth factor (VEGF) or platelet-derived growth factor (PDGF)-BB stimulation in vitro. In vivo, local application of VEGF to the adventitial side of the decellularized vessel increased re-endothelialization and reduced neointimal formation in samples at 4 weeks after implantation. A population of stem/progenitor cells exists within developing neointima, which displays the ability to differentiate into both endothelial and smooth muscle cells and can contribute to restenosis. Our findings also indicate that drugs or cytokines that direct cell differentiation toward an endothelial lineage may be effective tools in the prevention or delay of restenosis.     

In vivo characterization of bone marrow-derived fibroblasts recruited into fibrotic lesions

Fibroblasts, which are widely distributed and play a key part in tissue fibrosis, are phenotypically and functionally heterogeneous. Recent studies reported that bone marrow can be a source of tissue fibroblast. In the study reported here, we investigated in vivo characterization of bone marrow-derived fibroblasts recruited into various fibrotic lesions. Mice were engrafted with bone marrow isolated from transgenic mice expressing green fluorescent protein (GFP), and fibrotic lesions were induced by cancer implantation (skin), excisional wounding (skin), and bleomycin administration (lung). A small population of GFP+ fibroblast was found even in nonfibrotic skin (8.7% +/- 4.6%) and lung (8.9% +/- 2.5%). The proportion of GFP+ fibroblasts was significantly increased after cancer implantation(59.7% +/- 16.3%) and excisional wounding (32.2% +/- 4.8%), whereas it was not elevated after bleomycin administration (7.1% +/- 2.4%). Almost all GFP+ fibroblasts in fibrotic lesions expressed type I collagen, suggesting that bone marrow-derived fibroblasts would contribute to tissue fibrosis. GFP+ fibroblasts expressed CD45, Thy-1, and alpha-smooth muscle actin at various proportions. Our results suggested that bone marrow-derived fibroblasts expressed several fibroblastic markers in vivo and could be efficiently recruited into fibrotic lesions in response to injurious stimuli; however, the degree of recruitment frequency might depend on the tissue microenvironment.     

The evaluation of a small-diameter polysaccharide-based arterial graft in rats

Cardiovascular diseases may require surgery such as arterial bypasses that are usually performed with synthetic PTFE and Dacron grafts with diameter above 6mm. For smaller diameter replacement, healthy vascular tissue from the patient is not always available to carry out this type of graft. The purpose of this study was to evaluate the effectiveness of a small-diameter polysaccharide-based scaffold as an alternative arterial replacement. Tubular polysaccharide-based grafts of 2 mm internal diameter were prepared and moulded by a cross-linking technique. Fifteen Wistar adult rats underwent infrarenal aortic bypass with these grafts using microsurgical techniques. Grafts withstood aortic blood pressure and exhibited physiological blood flow, as evaluated with ultrasound techniques and angiographies at 4 and 8 weeks post-surgery. Harvested grafts were morphologically evaluated by light microscopy and immunohistochemistry. Neointima formation at 8 weeks was evidenced through collagen deposition and smooth muscle-like cells circumferential growth on the luminal surface without intimal hyperplasia or aneurysm formation. In conclusion, we described a 2mm polysaccharide-based arterial material being investigated in vivo and demonstrating patency for up to 8 weeks post-surgery with neointima formation and absence of intimal hyperplasia.     

Vascular tissue adaptations in end-to-end autologous arterial grafts in rats: a morphometric analysis

Autologous vein grafts are employed extensively to bypass stenoses in the arterial circulation. More recently arterial segments have been used for such bypass surgery. In this study the adaptation of regenerating vascular tissues in experimental autologous artery grafts (4 mm long and 1 mm in diameter) in 20 adult male Wistar rats was analysed. At 1, 2, 4, 8 and 16 wk after insertion, 4 grafts per time interval were removed, processed for high resolution light microscopy and the thicknesses of the media and neointima, as well as the area fractions of smooth muscle cells, were analysed morphometrically. All grafts were reendothelialised by 2 wk. Neointimal hyperplasia (a subendothelial layer of smooth muscle cells) developed in all grafts and reached its maximal thickness (40.4±4.7 μm) at 2 wk. The area fraction of smooth muscle cells in the neointima of the artery grafts did not change significantly at any time from 2 to 16 wk. The media underlying the neointima of the artery grafts remained relatively constant throughout the 16 wk duration of the experiment. Whilst the total wall thickness of the grafts reduced significantly between 2 and 4 wk after insertion, at all times the grafts were thicker than the host artery.     

Aortocoronary bypass graft in dogs: late histological changes.

Late histological changes occurring in aortocoronary bypass vein grafts were studied by lignt and electron microscopy in three dogs killed one, two and three years after grafting. The changes consisted of intimal thickening due to a proliferation of modified smooth muscle cells (myointimal hyperplasia) and replacement of most of the medial smooth muscle by fibrocytes. Serial angiography in the dogs did not reveal progression of the intimal thickening after one month.     

Vascular smooth muscle cells of recipient origin mediate intimal expansion after aortic allotransplantation in mice

Intimal expansion by vascular smooth muscle cells (SMCs) is a characteristic feature of graft vascular disease. Whether graft intimal SMCs arise from donor or recipient tissue is not well established but has important pathogenetic implications. We examined for the presence of male cells in the expanded intima of sex-mismatched mouse aortic allografts (C57BL/6-to-BALB/c) at 30 or 60 days after transplant by in situ hybridization using a Y-chromosome probe. Study groups included male-to-female allografts, female-to-male allografts, and female-to-female allografts in recipients previously engrafted with male bone marrow. Although intimal expansion developed in all allografts, male-to-female allografts lacked Y-chromosome-positive intimal cells. In contrast, such cells were abundant in female-to-male allografts and most of these cells co-labeled for smooth muscle alpha-actin by immunostain. Female-to-female allografts in recipients with male bone marrow showed a limited number of intimal Y-chromosome-positive cells. However, none of these clearly co-labeled for smooth muscle alpha-actin and their numbers declined throughout time, consistent with graft-infiltrating inflammatory cells. We conclude that intimal expansion of mouse aortic allografts is mediated by SMCs that originated from the recipient. There was little evidence of their derivation from the bone marrow, suggesting instead the adjacent host aorta as the primary source of intimal SMCs.     

自体移植兔静脉细胞增殖与钙激活钾通道的变化

目的: 研究静脉移植后钙激活钾通道(K_Ca)的变化,并探讨其病理生理意义。方法: 将兔的双侧股静脉倒置移植于同侧股动脉缺损之间,采用离体血管灌流的方法,测定移植静脉环的张力。分别以图像分析和四唑盐(MTT)比色法检测移植静脉内膜增厚的程度以及K_Ca的阻断剂盐酸四乙胺(tetraethylammonium chloride, TEA)对培养的家兔股静脉血管平滑肌细胞(vascular smooth muscle cells, VSMCs)增殖的影响。进而采用膜片钳技术记录K_Ca电流。 结果: 移植后1 week, 静脉的收缩性和内膜相对厚度没有显著变化。静脉移植后2 weeks,收缩性和内膜相对厚度显著大于对照组(P＜0.05, n=8)。移植后4 weeks静脉的收缩性和内膜相对厚度进一步大于对照组(P＜0.01, n=8)。TEA(2-8 mmol/L)显著增加培养VSMCs的MTT吸光值,并且有剂量依赖性(P＜0.05, n=8)。膜片钳实验结果显示,指令电位在(30-60)mV时,移植(1-4) weeks静脉VSMCs的K_Ca 电流密度均显著低于对照组(P＜0.05, n=5),指令电位在20 mV时,只有移植4 weeks静脉VSMCs的K_Ca电流密度显著低于对照组(P＜0.05, n=5)。结论: 自体移植静脉VSMC的K_Ca受到抑制,可能是血管收缩性增强、VSMCs异常增殖的原因,从而导致自体移植静脉痉挛和狭窄。     

Bone marrow-derived progenitor cells contribute to lung remodelling after myocardial infarction

BACKGROUND: Congestive heart failure (CHF) causes structural modifications of the lungs that contribute to the functional limitations of affected subjects. We hypothesized that bone marrow-derived progenitor cells could contribute to lung structural remodelling after myocardial infarction (MI). METHODS: Wistar rats were irradiated and received a bone marrow transplant (BMT) from green fluorescent protein (GFP) transgenic rats, followed 5 weeks later by coronary artery ligation or sham operation. Five weeks after MI, lung immunofluorescence studies were performed and GFP expression evaluated by Western immunoblotting. RESULTS: After MI, rats developed lung structural remodelling characterized by myofibroblast (MF) proliferation in the alveolar septa. After BMT, some GFP+ cells were found in the lungs of sham animals. The amount of GFP+ cells in the lungs of MI rats was greatly increased with evidence of differentiation into MFs, as evaluated by co-localization correlation analysis with smooth muscle alpha-actin (P<.01). These cells were particularly abundant in the perivenular regions where they incorporated into the wall of blood vessels. There was a threefold increase in lung GFP protein expression after MI (P=.01). CONCLUSIONS: After MI, bone marrow-derived progenitor differentiates into lung MFs. This novel pathophysiologic process may contribute to the pulmonary manifestations of CHF and could have significant therapeutic implications.