The role of vascular injury and hemodynamics in rat pulmonary artery remodeling.

Vascular remodeling in adult human elastic pulmonary arteries is characterized by diffuse neointimal lesions containing smooth muscle cells expressing extracellular matrix genes. Recent studies suggest vascular injury is needed to initiate remodeling and that growth factor mediators participate in the repair response. However, because neointimal formation is only observed in patients with pulmonary artery blood pressures approaching systemic levels, it has been hypothesized that systemic-like hemodynamic conditions are also necessary. To test that hypothesis, subclavian-pulmonary artery anastomoses were created in Sprague-Dawley rats under three different experimental conditions: no accompanying injury, or after monocrotaline or balloon endarterectomy injury. Pulmonary vascular remodeling was not induced by the subclavian-pulmonary artery anastomosis alone. A non-neointimal pattern of remodeling after mild monocrotaline-induced injury was converted into a neointimal pattern in the presence of the anastomosis. Neointima was also observed after severe, balloon endarterectomy-induced injury even in the absence of anastomosis. Tropoelastin, type I procollagen and TGF-beta gene expression, and angiotensin converting enzyme immunoreactivity, was confined to the neointima resembling the pattern of gene expression and immunoreactivity in human hypertensive elastic pulmonary artery neointimal lesions. These observations introduce the concepts that the type of injury and the associated hemodynamic conditions can modify the elastic pulmonary artery response to injury.

Transforming growth factor-beta 1 is decreased in remodeling hypertensive bovine pulmonary arteries.

The development of pulmonary hypertension in hypoxic newborn calves is associated with a complex pattern of increased tropoelastin and type I procollagen synthesis and deposition by smooth muscle cells in large elastic pulmonary arteries compared to normoxic controls. We examined the possibility that transforming growth factor-beta 1 (TGF-beta 1) may be associated with the production of extracellular matrix protein in this model of pulmonary hypertension. Medial smooth muscle cells in both normotensive and hypertensive vessels, as assessed by immunohistochemistry, were the major source of TGF-beta 1. Staining was confined to foci of smooth muscle cells in the outer media and appeared greater in normotensive than hypertensive vessels. Consistent with the immunohistochemistry, a progressive, age-dependent increase in normotensive pulmonary artery TGF-beta 1 mRNA was observed after birth, whereas TGF-beta 1 mRNA remained at low, basal levels in hypertensive, remodeling pulmonary arteries. These observations suggest that local expression of TGF-beta 1 is not associated with increased extracellular matrix protein synthesis in this model of hypoxic pulmonary hypertension.

Neointimal macrophages colocalize with extracellular matrix gene expression in human atherosclerotic pulmonary arteries.

Vascular remodeling in adult atherosclerotic pulmonary arteries is characterized by discrete areas of neointimal extracellular matrix gene expression, suggesting regulation by local factors. Though the factors responsible for inducing matrix gene expression in atherosclerotic lesions are largely unknown, several observations suggest macrophages may be a focal source of those factors. Immunohistochemistry confirmed the presence of macrophages in the neointima of atherosclerotic elastic pulmonary arteries from patients with unexplained pulmonary hypertension. Areas of neointima containing dense clusters of macrophages were separated by sparsely populated areas. Foamy macrophages resided more deeply within the neointima than nonfoamy macrophages, which were found more often subjacent to the endothelium or within the lumenal one-third of the neointima. Combined immunohistochemistry-in situ hybridization indicated neointimal fibronectin and type I procollagen gene expression was intimately associated only with nonfoamy neointimal macrophages. These observations suggest that: (a) nonfoamy neointimal macrophages participate in the local regulation of extracellular matrix gene expression in atherosclerotic pulmonary arteries; (b) foamy macrophages, which are not associated with matrix gene expression, have undergone modulation of their secretory phenotype.

Production and localization of 92-kilodalton gelatinase in abdominal aortic aneurysms. An elastolytic metalloproteinase expressed by aneurysm-infiltrating macrophages.

Abdominal aortic aneurysms (AAA) are characterized by disruption and degradation of the elastic media, yet the elastolytic proteinases involved and their cellular sources are undefined. We examined if 92-kD gelatinase, an elastolytic matrix metalloproteinase, participates in the pathobiology of AAA. Gelatin zymography of conditioned medium from normal, atheroocclusive disease (AOD), or AAA tissues in organ culture showed that all tissues produced 72-kD gelatinase. AOD and AAA cultures also secreted 92-kD gelatinase, but significantly more enzyme was released from AAA tissues. ELISA confirmed that AAA tissues released approximately 2-fold more 92-kD gelatinase than AOD tissue and approximately 10-fold more than normal aorta. Phorbol ester induced a 5.3-fold increase in 92-kD gelatinase secretion by normal aorta and AOD and an 11.5-fold increase by AAA. By immunohistochemistry, 92-kD gelatinase was not detected in normal aorta and was only occasionally seen within the neointimal lesions of AOD tissue. In all AAA specimens, however, 92-kD gelatinase was readily localized to numerous macrophages in the media and at the adventitial-medial junction. The expression of 92-kD gelatinase mRNA by aneurysm-infiltrating macrophages was confirmed by in situ hybridization. These results demonstrate that diseased aortic tissues secrete greater amounts of gelatinolytic activity than normal aorta primarily due to increased production of 92-kD gelatinase. In addition, the localization of 92-kD gelatinase to macrophages in the damaged wall of aneurysmal aortas suggests that chronic release of this elastolytic metalloproteinase contributes to extracellular matrix degradation in AAA.

Inhibition of inducible nitric oxide synthase ameliorates functional and histological changes of acute lung allograft rejection.

BACKGROUND: We recently demonstrated that inhibition of inducible nitric oxide synthase (iNOS) ameliorated severe acute lung allograft rejection. This study used a rat lung transplant model to determine (1) the time course and cellular localization of iNOS expression during the histological progression of unmodified acute rejection and (2) whether inhibition of iNOS prevented impaired gas exchange function of the allograft lung and/or ameliorated the histological changes of acute rejection. METHODS AND RESULTS: iNOS mRNA and enzyme activity were expressed in allograft lungs during mild, moderate, and severe acute rejection, but not in normal, isograft, or allograft lungs before histological changes of mild acute rejection. iNOS expression in allografts resulted in elevated serum nitrite/nitrate levels, indicative of increased in vivo nitric oxide (NO) production. In situ hybridization demonstrated iNOS mRNA expression in infiltrating inflammatory cells, but not in allograft parenchymal cells. Allografts had significantly impaired gas exchange, which was prevented with the selective iNOS inhibitor aminoguanidine (PaO2 of 566+/-19, 76+/-22, and 504+/-105 mmHg for isograft, allograft, and aminoguanidine-treated allograft, respectively; P<0.0002). Aminoguanidine also significantly improved the histological rejection scores. CONCLUSIONS: (1) iNOS expression and increased NO production occurred during the early stages of acute rejection, persisted throughout the unmodified rejection process, and localized to infiltrating inflammatory cells, but not allograft parenchymal cells; (2) aminoguanidine ameliorated the histological and functional changes of acute rejection; and (3) increased NO production, detected by the presence of iNOS mRNA, protein, or noninvasively by measuring serum nitrite/nitrate levels, may serve as an early marker of acute allograft rejection.

Criteria for outpatient management of proximal lower extremity deep venous thrombosis.

STUDY OBJECTIVES: To develop and to evaluate selection criteria for outpatient management of deep venous thrombosis (DVT). DESIGN: We developed outpatient treatment eligibility criteria that incorporated demographic and clinical data. We aimed to exclude patients at high risk for bleeding or recurrent clotting, as well as those with pulmonary embolism, limited cardiopulmonary reserve, or need for hospitalization due to another illness. Then, we retrospectively applied the criteria to hospitalized patients with newly diagnosed proximal lower extremity DVT to determine the fraction of patients eligible for outpatient therapy; patients were classified as eligible, possibly eligible, or ineligible for home treatment based on the selection criteria. SETTING: University hospital. PATIENTS: One hundred ninety-five hospitalized patients diagnosed as having proximal lower extremity DVT by duplex ultrasound over a 1-year period. MEASUREMENTS: Frequency of complications during initial DVT therapy, including major bleeding, symptomatic thromboembolism, and death. RESULTS: Eighteen (9%) patients were classified as eligible, and 18 (9%) were classified as possibly eligible for outpatient therapy. None of these patients developed complications. Of the 159 (82%) patients classified as ineligible, 13 (8%; 95% confidence interval [CI], 4 to 12%) died or developed serious complications. Therefore, the eligibility criteria had a sensitivity of 100% (95% CI, 92 to 100%) and a negative predictive value of 100% (95% CI, 92 to 100%) for predicting serious complications. CONCLUSIONS: Specific eligibility criteria may identify a subset of patients with acute DVT who can be treated safely at home.

Successful in vivo and ex vivo transfection of pulmonary artery segments in lung isografts.

OBJECTIVE: Gene transfer to lung grafts may be useful in ameliorating ischemia-reperfusion injury and rejection. Efficient gene transfection to the whole organ may prove problematic. Proximal pulmonary artery endothelial transfection might provide beneficial downstream effects on the whole graft. The aim of this study was to determine the feasibility of transfecting proximal pulmonary artery segments in lung isografts. METHODS: Male Fischer rats were divided into six groups. In vivo transfection: In group I (n = 7), a proximal segment of the left pulmonary artery was isolated and injected with saline solution by means of a catheter inserted through the right ventricle. After an exposure period of 20 minutes, clamps were removed and blood flow was restored. In group II (n = 7), the isolated arterial segments were injected with adenovirus carrying the Escherichia coli LacZ gene encoding for beta-galactosidase. Ex vivo transfection: In group III (n = 5), arterial segments were injected ex vivo with saline solution and in group IV (n = 5) with the adenovirus construct. In group V (n = 6), arteries were injected with saline solution and in group VI (n = 11) with liposome chloramphenicol acetyl transferase cDNA. In groups I to IV, animals were killed on postoperative day 3 and transgene expression was assessed by Bluo-Gal staining. In groups V and VI, animals were killed on postoperative day 2 and transgene expression was assessed by chloramphenicol acetyl transferase activity assay. RESULTS: Transgene expression was detected grossly and microscopically in endothelial and smooth muscle cells of pulmonary artery segments from all surviving animals of groups II and IV. In group VI, chloramphenicol acetyl transferase activity was significant in all assessed arterial segments. CONCLUSION: Significant transgene expression is observed in proximal pulmonary artery segments after both in vivo and ex vivo exposure.

Liposome-mediated gene transfer to lung isografts.

OBJECTIVES: Our objective were to determine the feasibility, efficacy, and safety of in vivo and ex vivo liposome-mediated gene transfer to lung isografts. METHODS: Fischer rats were divided into three main groups: (1) Nontransplant setting: Liposome-chloramphenicol acetyl transferase cDNA was intravenously injected, and lungs were harvested at different time points: 2, 6, 12, and 24 hours; 2, 5, 8, and 21 days (n = 3). Chloramphenicol acetyl transferase activity was determined in lungs, hearts, livers, and kidneys. The distribution and type of transfected cells were evaluated by in situ hybridization. Lung toxicity was assessed by arterial oxygen tension, histology, and tumor necrosis factor-alpha levels. (2) In vivo graft transfection: Left lungs were transplanted 6 hours, 4 hours, and 15 minutes after intravenous injection and were assessed for chloramphenicol acetyl transferase activity and arterial oxygen tension on postoperative day 2. (3) Ex vivo graft transfection: Grafts were infused ex vivo with either 660 micrograms (n = 3) or 330 micrograms (n = 3) of DNA complexed to liposomes and stored at 10 degrees C for 4 hours. Chloramphenicol acetyl transferase activity was assessed 44 hours after transplantation. RESULTS: Transgene expression was detected in endothelial cells, macrophages, and interstitial cells. Chloramphenicol acetyl transferase activity was present as early as 2 hours, increased significantly between 6 hours and 8 days, and then decreased to minimal levels by 21 days. Chloramphenicol acetyl transferase activity was greatest in donor lungs and hearts and minimal in livers and kidneys. Arterial oxygen tension was normal in treated animals. Inflammation was minimal, and tumor necrosis factor-alpha levels increased only sevenfold in treated animals. CONCLUSION: In vivo and ex vivo liposome-mediated gene transfer to lung isografts allows significant transgene expression with minimal effects on graft function.

Time course and cellular localization of inducible nitric oxide synthases expression during cardiac allograft rejection.

BACKGROUND: We have demonstrated that inhibition of inducible nitric oxide synthase (NOS) ameliorated acute cardiac allograft rejection. This study determined the time course and cellular localization of inducible NOS expression during the histologic progression of unmodified acute rat cardiac allograft rejection. METHODS: Tissue from syngeneic (ACI to ACI) and allogeneic (Lewis to ACI) transplants were harvested on postoperative days 3 through 10 and analyzed for inducible NOS mRNA expression (ribonuclease protection assay), inducible NOS enzyme activity (conversion of L-[3H]arginine to nitric oxide and L-[3H]citrulline), and nitric oxide production (serum nitrite/nitrate levels). Inducible NOS mRNA and protein expression were localized using in situ hybridization and immunohistochemistry. RESULTS: Inducible NOS mRNA and enzyme activity were expressed in allografts during mild, moderate, and severe acute rejection (postoperative days 4 through 10), but were not detected in normals, isografts, or allografts before histologic changes of mild acute rejection (postoperative day 3). Inducible NOS expression resulted in increased serum nitrite/nitrate levels during mild and moderate rejection (postoperative days 4 through 6). Inducible NOS mRNA and protein expression localized to infiltrating mononuclear inflammatory cells in allograft tissue sections during all stages of rejection but were not detected in allograft parenchymal cells or in normals or isografts. CONCLUSIONS: Inducible NOS expression and increased nitric oxide production occurred during the early stages of acute rejection, persisted throughout the unmodified rejection process, and localized to infiltrating inflammatory cells but not allograft parenchymal cells during all stages of acute rejection.

Adenovirus mediated gene transfer into rat lung grafts at the time of harvest.

OBJECTIVE: New methods to introduce genetic material into cells in vivo may revolutionize current treatment modalities. Expression of functional genes in lung allografts could be used as a prophylactic strategy for reperfusion injury and rejection. We studied the feasibility of ex vivo adenovirus mediated transfection of rat lung allografts. METHODS: In group I (n = 3) donor rat lungs (Fisher) were flushed with Low Potassium Dextran Glucose (LPDG) solution (20 ml, 20 degrees C). 4 x 10(11) viral particles of adenovirus 5 containing the E. coli lacZ reporter gene coding for beta-galactosidase (AdCMV-beta-Gal) were added to the last milliliter of the flush solution. Lung grafts were stored for 3.5 h at room temperature followed by syngenic orthotopic transplantation (Fisher to Fisher) using a microsurgical cuff technique. On postoperative day 5 the heart lung block was extracted and flushed with x-Gal (beta-Gal substrate) and kept in x-Gal for 3 h at 37 degrees C. Color development was observed macroscopically and plastic embedded sections were used for histologic examination. Group II grafts (n = 3) served as controls and were flushed without adenovirus. RESULTS: X-Gal stained the transfected lung grafts blue, indicating high reporter gene expression. Control lungs did not stain with x-Gal. In group I histological examination demonstrated transfection predominantly in type II pneumocytes. Surprisingly endothelial cells showed no beta-Gal activity. CONCLUSION: This study demonstrates that ex vivo transfection of lung grafts at the time of harvest is a feasible method of gene transfer and results in gene expression after transplantation.

Pulmonary artery aneurysm: review and case report.

Aneurysms involving the main pulmonary artery and its branches are rare. Clinical experience is limited and current knowledge is mainly derived from autopsy findings. This case report describes a patient with a pulmonary artery aneurysm associated with a previous, partially corrected stenotic pulmonary valve. The patient presented with symptoms suggestive of aneurysm dissection three decades after commissurotomy. The diagnostic approach and therapeutic intervention are emphasized with a review of the literature.

Vascular remodeling in primary pulmonary hypertension. Potential role for transforming growth factor-beta.

Active exogenous transforming growth factor-beta s (TGF-beta s) are potent modulators of extracellular matrix synthesis in cell culture and stimulate matrix synthesis in wounds and other remodeling tissues. The role of endogenous TGF-beta s in remodeling tissues is less well defined. Vascular remodeling in the pulmonary arteries of patients with primary pulmonary hypertension is characterized, in part, by abnormal deposition of immunohistochemically detectable procollagen, thereby identifying actively remodeling vessels. We used this marker of active matrix synthesis to begin defining the in vivo role of TGF-beta in the complex milieu of actively remodeling tissues. Immunohistochemistry using isoform-specific anti-TGF-beta antibodies was performed to determine whether TGF-beta was present in actively remodeling hypertensive pulmonary arteries 20 to 500 microns in diameter. Intense, cell-associated TGF-beta 3 immunoreactivity was observed in the media and neointima of these hypertensive muscular arteries. Immunostaining was present, but less intense, in normal arteries of comparable size. TGF-beta 2 immunoreactivity was observed in normal vessels and was increased slightly in hypertensive vessels, in a pattern resembling TGF-beta 3 immunoreactivity. No staining was associated with the adventitia. TGF-beta 1 immunostaining was either faint or absent in both normal and hypertensive vessels. Comparison of procollagen and TGF-beta localization demonstrated that TGF-beta 2 and TGF-beta 3 colocalized at all sites of procollagen synthesis. However, TGF-beta was observed in vessels, or vascular compartments, where there was no procollagen synthesis. Procollagen immunoreactivity was not present in normal vessels that showed immunoreactivity for TGF-beta 2 and TGF-beta 3. These observations suggest: a) the stimulation of procollagen synthesis by TGF-beta in vivo is more complex than suggested by in vitro studies and b) a potential role for TGF-beta 2 or TGF-beta 3, but not TGF-beta 1, in hypertensive pulmonary vascular remodeling.

Care of patients with deep venous thrombosis in an academic medical center: limitations and lessons.

PURPOSE: The primary goal of our study was to review the quality of care in patients with deep vein thrombosis,, with emphasis on identifying recurrent and remedial problems. Secondary goals were (1) to evaluate the use of the vascular laboratory and (2) to characterize our patient population with deep vein thrombosis and to identify a subset of patients with uncomplicated deep vein thrombosis who might be candidates for outpatient therapy in the future. METHODS: A retrospective review was performed for all patients with deep vein thrombosis diagnosed with duplex scanning who were treated as inpatients from January 1993 through March 1993. RESULTS: Fifty-four (16%) of 306 duplex scans were positive; 50 patients were treated as inpatients. Forty percent of patients had uncomplicated deep vein thrombosis that was potentially treatable on an outpatient basis. Mean time to obtain a therapeutic partial thromboplastin time was 22 hours (range 4 to 54 hours). Ten (20%) patients had inferior vena cava filters placed. The in-hospital mortality rate was 4%. Management problems occurred in 18 (36%) patients and included difficulty titrating anticoagulation, (10) physician failure to provide treatment after diagnosis, (five) and inappropriate use or complication of inferior vena cava filter placement (three). CONCLUSIONS: Venous duplex examination is liberally but appropriately used. The primary remediable problem resulting in suboptimal management is difficulty titrating anticoagulation; inappropriate placement of inferior vena cava filters and physician failure to provide treatment also occur. In the future a substantial number of patients may be suitable for outpatient therapy.

Angiotensin converting enzyme expression in primary pulmonary hypertension.

We compared immunoreactivity for angiotensin converting enzyme (ACE) in pulmonary artery and lung parenchymal tissues (obtained at the time of resection for lung transplantation) from eight patients with Stage IV primary pulmonary hypertension (PPH) with the reactivity in similar tissues from eight normal donors. ACE immunoreactivity was markedly and consistently increased in the endothelium and subendothelial neointimal regions of elastic pulmonary arteries from patients with PPH as compared with normal pulmonary arteries. Immunoreactivity in normal muscular pulmonary arteries was usually less than in surrounding capillary endothelial cells, whereas it was usually of comparable intensity with that in surrounding alveolar capillaries in muscular pulmonary arteries of patients with PPH. These observations suggest that ACE may be involved in the pathogenesis of vascular remodeling associated with neointimal formation in pulmonary arteries.

Inhibition of tropoelastin expression by 1,25-dihydroxyvitamin D3.

Elastin production is modulated by steroid hormones and is dependent on calcium. Because vitamin D3 is involved in the regulation of calcium metabolism and influences the expression of various extracellular matrix proteins, we investigated whether vitamin D3 influences tropoelastin expression. Three elastin-producing, bovine cell types, auricular chondroblasts, nuchal ligament fibroblasts and arterial smooth muscle cells, were treated with the principal active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), and with 24,25 dihydroxyvitamin D3 (24,25[OH]2D3). Tropoelastin levels in culture media and cell layers, as measured by an enzyme-linked immunoassay, decreased in a dose and exposure dependent manner after treatment with 1,25(OH)2D3; 24,25(OH)2D3 had no effect on tropoelastin production relative to solvent-treated controls. The maximal effective dose of 1,25(OH)2D3 was 10(-7) M for 48 hr, which resulted in a severalfold reduction of tropoelastin production, and decreased tropoelastin levels were detected at 8 hr after treatment. Reduction of tropoelastin protein production was paralleled by a decrease of equal magnitude in the steady-state levels of tropoelastin mRNA. Vitamin D3 metabolites had no effect on DNA or total protein synthesis. These results suggest that vitamin D3 may be an important modulator of elastin expression.

Submucosal collagen in experimental gastroschisis.

Gastroschisis is a congenital anomaly in which the intestines are exposed to amniotic fluid throughout fetal life. Previous studies in animal models have demonstrated smooth muscle thickening and decreased contractility, epithelial dysfunction, and submucosal thickening. The present studies were done to further define the mechanism of submucosal changes by investigating collagen deposition and gene expression in a rabbit model. Gastroschisis was surgically created in fetal rabbits at 24 days gestation (term is 31 days). Sham-operated and unoperated fetuses served as controls. Fetuses were sacrificed and bowels were harvested at 26, 28, and 31 days gestation. Animal weight and gross and histologic appearance were assessed. Submucosal collagen content was measured using the van Geison stain. In situ hybridization of the expression of alpha (1) procollagen RNA was done to determine the distribution and source of submucosal collagen. At term, submucosal thickening was present in animals with gastroschisis, associated with a significantly increased collagen content. Collagen distribution was also more diffuse in the gastroschisis animals than in controls. In situ hybridization revealed procollagen expression in round cells located in the submucosa and not in smooth muscle. These cells did not resemble fibroblasts, and their identity is uncertain. Experimental gastroschisis is characterized by submucosal thickening which is associated with changes in collagen, including increased deposition and more diffuse distribution in the submucosa. The cells responsible for production of procollagen are round, nonfibroblast cells which are located in the submucosa and not in the smooth muscle layer. These findings may have some importance in understanding the mechanisms responsible for intestinal malfunction in infants with gastroschisis.

Pulmonary hemodynamics modify the rat pulmonary artery response to injury. A neointimal model of pulmonary hypertension.

Hemodynamic factors have profound influences on blood vessels. To test the hypothesis that hemodynamic conditions modify the pattern of remodeling in response to injury, monocrotaline (MCT) injury in Sprague-Dawley rats was followed 1 week later by left pneumonectomy to increase blood flow to the right lung. Right pulmonary artery remodeling in these MCT plus pneumonectomy animals was compared with animals receiving MCT or pneumonectomy alone. Neointimal changes developed in more than 90% of all right lung intra-acinar vessels 5 weeks after MCT injury (4 weeks after pneumonectomy). Neointimal lesions did not develop in untreated animals or in animals receiving MCT or pneumonectomy only. Animals with a neointimal pattern of remodeling developed severe right ventricular hypertrophy (RVH) whereas animals with a medial hypertrophy pattern of remodeling (MCT only) developed moderate RVH compared with control animals. Neointimal lesions and RVH were similar whether injury preceded pneumonectomy or vice versa. To exclude the possibility that neointimal lesions resulted from injury plus post-pneumonectomy compensatory lung growth, rather than injury plus increased flow, a left subclavian-pulmonary artery anastomosis was substituted for pneumonectomy. Neointimal lesions and severe RVH developed in these animals but were not seen in animals receiving either MCT or anastomosis only. These studies demonstrate an important role for hemodynamics in determining the pattern of pulmonary vascular remodeling after injury.

Angiotensin-converting enzyme inhibition delays pulmonary vascular neointimal formation.

Primary pulmonary hypertension (PPH) is a disease characterized pathologically by pulmonary artery medial hypertrophy, adventitial thickening, and neointimal proliferation. Increasing recognition of the importance of remodeling to the pathogenesis of PPH suggests new therapeutic possibilities, but it will be necessary to (1) identify essential mediators of remodeling, and (2) demonstrate that inhibiting those mediators suppresses remodeling before new antiremodeling therapies can be considered feasible. The effect of angiotensin-converting enzyme (ACE) inhibition on pulmonary vascular remodeling was studied in a newly developed rat model in which neointimal lesions develop between 3 and 5 wk after monocrotaline injury is coupled with increased pulmonary artery blood flow after contralateral pneumonectomy. Neointimal formation was significantly suppressed at 5 wk by ACE inhibition whether it was started 10 d before or 3 wk after remodeling was initiated, although medial hypertrophy and adventitial thickening still developed. By 11 wk, the extent of neointimal formation in rats treated with ACE inhibition was similar to rats without ACE inhibition at 5 wk. Pulmonary artery pressures and right ventricular weights correlated with the extent of neointimal formation. Northern blot analysis and in situ hybridization demonstrated marked suppression of lung tropoelastin and type I procollagen gene expression in the presence of ACE inhibition. An angiotensin II type I receptor antagonist partially, but not completely, replicated the effects of ACE inhibition. These data suggest that the tissue angiotensin system may be a target for therapeutic efforts to suppress the vascular remodeling that is characteristic of primary pulmonary hypertension.