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Departments of 1 Pediatrics and 2 Molecular Pharmacology, Northwestern University, Chicago, Illinois 60614; 3 Department of Pediatrics and Cardiovascular Research Institute, University of California, San Francisco, California 94143-0130; and Departments of 4 Pediatrics and 5 Physiology, State University of New York at Buffalo, New York 14214-3078
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Congenital heart disease associated with increased pulmonary blood flow produces pulmonary hypertension. To characterize vascular alterations in the nitric oxide (NO)-cGMP cascade induced by increased pulmonary blood flow and pulmonary hypertension, 10 fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). When the lambs were 4-6 wk of age, we assessed responses of pulmonary arteries (PAs) and pulmonary veins (PVs) isolated from lungs of control and shunted lambs. PVs from control and shunted lambs relaxed similarly to exogenous NO (S-nitrosyl-acetyl-penicillamine), to NO produced endogenously (zaprinast and A-23187), and to cGMP (atrial natriuretic peptide). In contrast, relaxations to A-23187 and zaprinast were blunted in PAs isolated from shunted lambs relative to controls. Inhibitors of NO synthase (NOS) and soluble guanylate cyclase constricted control but not shunt PAs, indicating reduced basal NOS activity in shunt PAs. Pretreatment of shunt PAs with the substrates L-arginine and sepiapterin, a precursor for tetrahydrobiopterin synthesis, did not augment A-23187 relaxations. However, pretreatment with superoxide dismutase and catalase significantly enhanced A-23187 relaxations in shunt PAs. We conclude that increased pulmonary blood flow induces an impairment of endothelium-dependent relaxation that is selective to PAs. The impaired relaxation may be mediated in part by excess superoxide production.
endothelial nitric oxide synthase; superoxide; circulation; artery
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE REGULATION of
normal pulmonary vascular tone is a complex process that is regulated
in part by vasoactive substances produced by the vascular endothelium
(7). Nitric oxide (NO), a gaseous free radical, is
produced from the terminal nitrogen of L-arginine by NO
synthase (NOS). There are three known isoforms of NOS in mammals, and
all three isoforms are present and developmentally regulated in the
fetal rat lung (13, 18). Specific stimuli such as shear
stress and the receptor binding of specific endothelium-dependent vasodilators activate a constitutively expressed endothelial NOS (eNOS)
to synthesize and release NO. The best-described vascular action of NO
is its activation of soluble guanylate cyclase, a heterodimer with
1- and 
1-subunits. This in turn results
in increased smooth muscle cell concentrations of cGMP and activation of protein kinase G. Cyclic nucleotide phosphodiesterases constitute the only known pathway for the hydrolysis of cGMP and therefore control
the intensity and duration of its signal transduction. A cGMP-specific
phosphodiesterase (PDE5) is found in especially high concentrations in
the lung (14). In addition to properties of vasodilation,
NO and cGMP inhibit smooth muscle mitogenesis (8).
Congenital heart disease associated with increased pulmonary blood flow and/or increased pulmonary venous pressure commonly leads to the development of pulmonary hypertension and its associated increased vascular reactivity (11). The risk and timing of developing pulmonary hypertension is dependent on a variety of factors, including the age of the patient and the particular heart defect. Endothelial injury induced by increases in flow or pressure has been proposed as an important factor in the development of pulmonary hypertension. For example, adults with advanced pulmonary hypertension have impaired endothelium-dependent pulmonary vasodilation and decreased eNOS gene expression within pulmonary vascular endothelial cells (5, 9). However, because most patients who undergo histological evaluation have advanced pulmonary hypertension, it has been difficult to investigate early aberrations in the NO-cGMP cascade and to determine the potential role of these aberrations in the development of pulmonary hypertension secondary to increased pulmonary blood flow.
We recently established a unique animal model of pulmonary hypertension that mimics congenital heart disease with increased pulmonary blood flow (15) by placing aortopulmonary shunts in the fetal lamb. In vivo these intact lambs have physiological alterations in the NO-cGMP cascade and selective impairment of endothelium-dependent pulmonary vasodilation by 4 wk of age (16). However, we recently reported that expression of eNOS is increased in pulmonary arteries (PAs) isolated from these lambs (2). The purpose of the present study was to further localize and determine potential mechanisms for the impairment in endothelium-dependent relaxation by assessing functional responses in fifth-generation PAs and pulmonary veins (PVs) isolated from control and shunted lambs.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Surgical preparations and care. This study was approved by the State University of New York at Buffalo Laboratory Animal Care Committee. Ten pregnant ewes (137-141 days gestation, term = 145 days) were operated on under sterile conditions as previously described (15). Through a left lateral fetal thoracotomy, an 8.0-mm Gore-Tex vascular graft (~2 mm length) (W. L. Gore, Milpitas, CA) was anastomosed between the ascending aorta and the main PA of the fetus with 7.0 proline (Ethicon, Somerville, NJ) using a continuous suture technique (15). After recovery from anesthesia the ewe was returned to the cage with free access to food and water. Antibiotics (2,000,000 units of penicillin G potassium and 100 mg of gentamicin sulfate) were administered to the ewe during surgery and daily thereafter until 2 days after spontaneous delivery of the lamb.
After spontaneous delivery, antibiotics (1,000,000 units of penicillin G potassium and 25 mg of gentamicin sulfate im) were administered to the lambs for 2 days. The lambs were weighed daily, and respiratory and heart rates were measured. Furosemide (1 mg/kg im) was administered daily. Elemental iron (50 mg im) was given weekly. At age 4 wk, pentobarbitol sodium (
30 mg/kg iv) was given to lambs as needed to
maintain adequate anesthesia. The lambs were immediately killed by
rapid exsanguination through a cardiac puncture.
Vessel isolation. The heart and lungs were removed en bloc from the thorax immediately after death and placed in Krebs-Ringer solution (in mM: 118 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, 25.5 NaHCO3, 5.6 glucose, and 0.026 calcium disodium EDTA). Fifth-generation intralobar PAs with inside diameters of 0.5-1.5 mm were isolated, dissected with care to preserve the integrity of the endothelium, and cut into rings ~2-3 mm long and 1-3 mg in weight. Wet tissue weights were obtained at the end of each experiment after the rings were blotted dry on gauze pads. The force of contraction was normalized by the weight of each ring and is expressed as grams per gram of tissue (g/g).
Vessel rings were mounted on stainless steel hooks and placed in water-jacketed chambers. Tissues were bathed with 6 ml of Krebs-Ringer solution, which was maintained at 37oC and aerated with a gas mixture of 94% O2-6% CO2 to maintain pH 7.40, PCO2 = 38 Torr, and PO2 > 500 Torr. A continuous recording of isometric force generation was obtained by tying each vessel ring to a force-displacement transducer (Statham UC 2, Statham Instruments, Hato Rey, PR) that was connected to an oscillographic recorder. Once mounted, the vessel rings were allowed to equilibrate for 20 min in the bathing solution. A micrometer was then used to stretch the tissues repeatedly in small increments over the next 45 min until resting tone remained stable at a passive tension of 1.0 g for control arteries and 1.2 g for arteries from hypertensive lambs. Preliminary experiments determined that this was the optimal length for generation of active tone in response to exogenous norepinephrine (NE).Experimental protocols.
The following pharmacological agents were used:
L-norepinephrine hydrochloride, indomethacin,
DL-propranolol hydrochloride, N
-nitro-L-arginine
(L-NNA), calcium ionophore A-23187, ACh,
S-nitroso-N-acetyl-penicillamine (SNAP), atrial
natriuretic peptide (ANP),
1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ), zaprinast,
L-arginine, sepiapterin, polyethylene glycol-superoxide dismutase (PEG-SOD), and polyethylene glycol-catalase (PEG-CAT). All
drugs were purchased from Sigma Chemical (St. Louis, MO) except for
zaprinast, which was a gift from Rhone-Poulenc (Dagenham Essex, UK).
Drugs were dissolved in distilled H2O, except
L-NNA, which was dissolved directly in Krebs-Ringer
solution due to the high bath concentrations used, and indomethacin,
which was dissolved in ethanol. Ethanol, at the concentrations used in
these experiments, did not alter the preexisting tone of PAs or PVs.
Drugs were made fresh daily.
5 M
indomethacin to prevent the formation of vasoactive prostaglandins and
with 106 M propranolol to block -adrenergic receptors.
To examine the effect of dilator agents, PVs were first preconstricted
with an EC50 (the concentration required to achieve 50% of
maximum constriction) of NE (3 × 107 M). The
EC50 for NE was determined from preliminary studies in which cumulative concentration-response curves for NE
(108-105 M) were developed in both arteries
and veins. Once the response to NE had reached a steady level,
cumulative concentration-response curves to dilator agents were
obtained by increasing the bath concentration of these drugs in
successive steps: the next concentration was added only when the
response to the prior concentration had reached a plateau. Vessel rings
were used for one experimental protocol and then discarded.
In some protocols tissues were pretreated with the competitive NOS
inhibitor L-NNA (103 M) in addition to
prostaglandin inhibitors. Because of the sensitivity of
L-NNA to light, all experiments were performed in a
darkened room and tissue baths were wrapped in aluminum foil.
In all experiments, n represents the number of animals from
which vessel rings were studied. Data are expressed as the means ± SE. Statistical analysis was performed with StatView 4.5 software (Abacus Concepts, Berkley, CA). Statistical comparisons were performed on concentration-response curves using repeated-measures ANOVA and
Student-Newman-Keuls test for post hoc testing of multiple comparisons
as appropriate. Individual data points between curves were compared
using one-way ANOVA and Student-Newman-Keuls testing for multiple
comparisons as needed. Significance was accepted at P < 0.05.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Relaxations to A-23187 and zaprinast were used to test for
responsiveness to endogenously produced NO. Figure
1 shows that PAs from shunted lambs
relaxed significantly less to 3 × 107 M A-23187
than did PAs isolated from control lambs (32 ± 7% vs. 79 ± 8%; P < 0.05). In the PVs, relaxations induced by
A-23187 were similar in shunted and control lambs. Figure
2 shows a similar pattern of
responsiveness to zaprinast. In addition, preliminary experiments
(n = 3 for control and shunt, data not shown) revealed that PA relaxation responses to the receptor-dependent agonist ACh were
similar in pattern to the receptor-independent agonist A-23187.
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PAs and PVs from both control and shunted lambs relaxed similarly and
completely to SNAP (Fig. 3). In addition
PAs and PVs from control and shunted lambs relaxed similarly to
increasing concentrations of ANP (Fig.
4).
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Plateau contractile responses to NE were not significantly different in
PAs or PVs isolated from shunted lambs first incubated with
indomethacin and propranolol and then constricted with increasing concentrations of NE (Fig. 5). In further
experiments, pretreatment with 103 M L-NNA
was used to test for the effect of endogenously produced NO.
Constrictions to NE were significantly enhanced after pretreatment with
L-NNA in control and shunt PVs and control PAs but not in PAs from shunted lambs (Fig. 5). Further experiments used increasing concentrations of the soluble guanylate cyclase inhibitor ODQ after
preconstriction with NE. Control vessels constricted significantly to
increasing concentrations of ODQ, however, shunt vessels did not (Fig.
6).
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To begin to elucidate the mechanism for the impairment in
endothelium-dependent relaxation, PAs were pretreated with
L-arginine (103 M) or sepiapterin
(104 M). Neither agent enhanced relaxations to threshold
or maximal concentrations of A-23187 in shunt PAs (Fig.
7) or control PAs (data not shown).
Finally, PAs from control and shunted lambs were pretreated with the
combination of PEG-SOD (37.5 U/ml) and PEG-CAT (1,200 U/ml) before
relaxation with A-23187. Pretreatment with SOD-CAT did not alter
relaxations to A-23187 in control PVs but did significantly enhance
relaxations to A-23187 in PVs from shunted lambs (Fig.
8).
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The development of pulmonary hypertension and its associated altered reactivity is a major source of morbidity and mortality in children with congenital heart disease. There are two major types of defects that induce pulmonary hypertension: those with increased pulmonary blood flow that result in increased arterial pressure, and those with left-sided obstruction that result in increased venous pressure. Although the vascular smooth muscle morphology is similar in advanced disease, early functional differences between arteries and veins during pulmonary hypertension have not been well studied. Increasing data suggest that aberrations in endothelial function participate in the pathophysiology of pulmonary hypertension. To begin to investigate early aberrations in endothelial function during the development of pulmonary hypertension, we developed an animal model of increased pulmonary blood flow in the lamb after in utero placement of an aorta-to-pulmonary vascular graft. Previously we demonstrated a selective impairment in endothelium-dependent pulmonary vasodilation in intact 4-wk-old lambs (16). In the present study we utilized isolated vessel techniques to determine functional differences between PAs and PVs as well as their potential mechanisms. The present data suggest that increased pulmonary blood flow induces an impairment of endothelium-dependent relaxation that is selective to the PAs. In addition, the impaired relaxation is not secondary to altered L-arginine or cofactor availability but is mediated in part by excess superoxide production.
To assess potential early alterations in endothelium-dependent vasodilation secondary to increased pulmonary blood flow, we evaluated NO-dependent vasoactive responses in PAs and PVs isolated from control lambs and lambs with high pulmonary blood flow due to an aortopulmonary shunt at age 4 wk. In vivo we previously demonstrated that the pulmonary vasodilating effects of ACh and ATP, both endothelium-dependent vasodilators, were significantly attenuated compared with age-matched controls with a similar degree of pulmonary hypertension induced by U-46619 (16). The effects of inhaled NO were similar in both groups of lambs. In the current isolated vessel study, we chose A-23187 instead of ACh as an agonist for NOS because its action is independent of receptor function. In addition, unlike ACh, A-23187 does not produce vasoconstriction in PVs from juvenile lambs (21). We observed a selective impairment of endothelium-dependent relaxation in shunted lambs and also demonstrated that the disruption was specific to the PAs. We found that relaxations to A-23187 and zaprinast were attenuated in shunt PAs but were similar in PVs.
In vivo both the arteries and veins are exposed to similar amounts of increased pulmonary blood flow. However, there is a large pressure drop across the pulmonary capillary bed, such that the pressure in the arteries is much greater than the veins. These data therefore suggest that the impairment in endothelium-dependent relaxation is secondary to exposure to increased pressure in addition to increased flow. To begin to further determine potential mechanisms for the selective impairment in endothelium-dependent relaxation, we attempted to restore relaxations to A-23187 by the addition of L-arginine, sepiapterin (a precursor for synthesis of the essential NOS cofactor tetrahydrobiopterin), or the combination of SOD-CAT. Several biological systems have suggested that depletion of critical substrates is a potential mechanism for decreased NOS activity (3, 4, 10, 12). However, in the present study pretreatment with an excess of L-arginine or sepiapterin did not restore endothelium-dependent relaxations, suggesting that substrate depletion was not the mechanism for decreased NO activity in our isolated vessels. However, it is still possible that longer term in vivo supplementation might produce different results (10).
Previously we demonstrated an upregulation of NOS expression in shunted lambs (2). However, in the current study we observed blunted relaxations to zaprinast as well as blunted constrictions to L-NNA and ODQ in PAs from shunted lambs. Constrictions to L-NNA reflect removal of NO, and constrictions to ODQ reflect inhibition of cGMP production by soluble guanylate cyclase. Therefore, we found no functional evidence for increased basal NO production by NOS in vessels isolated from shunted lambs relative to controls. Our data indicate decreased functional basal and stimulated activity of NOS despite our previous findings of increased expression. We therefore considered the possibilities that NOS was not functional, or that NOS was functional and that the NO produced was inactivated by another agent.
When endothelial cells are subjected to shear stress, a complex set of responses is initiated that includes changes in gene expression (17). Shear stress is proportional to the velocity of blood and its viscosity and inversely proportional to the internal radius of the blood vessel to the third power. Because the pulmonary circulation of shunted lambs is exposed to increased pulmonary blood flow and the PAs have a decreased internal radius secondary to vascular remodeling, shear stress is most likely increased, and this increase is sustained over time in shunted lambs. Increases in shear stress stimulate endothelial cells to produce several modulators of vascular tone in addition to NO. One such agent is superoxide, a free radical implicated in producing endothelial dysfunction in a variety of biological systems. Superoxide production is possible from several sources, including xanthine oxidase, NADPH oxidase, or even NOS under specific conditions (1, 22). In addition, increased exogenous NO has been reported to increase cellular superoxide generation, which in turn inhibits NOS activity (19). We found that pretreatment of vessels with membrane-permeable SOD-CAT enhanced relaxations to A-23187 in PAs from shunted but not control lambs. These data suggest superoxide and/or peroxynitrite formation are at least partially responsible for the impairment in endothelium-dependent relaxations displayed in shunted lambs.
Previously we demonstrated that mRNA expression and protein content of eNOS were significantly increased in shunted lambs relative to controls (2). In situ hybridization and immunohistochemistry localized these increases to the endothelium of small and large PAs. The size of vessels used in our current study was well within the vessel size used to determine NOS expression. In fact, Western blot analysis of these isolated vessels demonstrated that the increase in eNOS protein was isolated to the PAs and was unchanged in the PVs. These data suggest that eNOS may be a source for the superoxide-mediated impaired relaxations. All vessels were aerated with a gas mixture that produced hyperoxic conditions. Although pretreatment with SOD-CAT did not alter relaxations in the control PAs, it is possible that these hyperoxic conditions amplified superoxide production in the shunt PAs.
Relaxations to exogenous NO in the form of SNAP and to ANP, which produces cGMP by the particulate guanylate cyclase pathway, were not different in either the PAs or PVs of shunted lambs. These data suggest that no difference in functional activity of soluble guanylate cyclase or in mechanisms of relaxation to cGMP exists in either the PAs or PVs. Vascular relaxations to cGMP-specific phosphodiesterase inhibitors such as zaprinast are dependent on basal endothelial NO production as well as on endogenous phosphodiesterase activity (6). We previously reported an 80% increase in expression of PDE5 in shunted lambs (2). Increased functional activity of PDE5 would be expected to enhance cGMP clearance and therefore blunt relaxations to cGMP generated in response to NO and ANP. However, we found no difference between PAs isolated from control and shunted lambs in relaxations to NO and ANP in the current study or in previous studies; therefore it is unlikely that the decreased relaxations to zaprinast were the result of altered phosphodiesterase activity. Instead we conclude that these decreased relaxations are most likely due to decreased functional eNOS activity in the shunt vessels, leading to decreased NO and cGMP production. Finally, because A-23187 is a receptor-independent agonist, the impairment in endothelium-dependent relaxations we previously demonstrated to ACh in vivo does not appear to be secondary to alterations in receptor function.
Although we were not able to directly compare NO production in our isolated PVs, it seems likely that endothelial dysfunction associated with excess superoxide production interferes with the vascular relaxing effects of NO produced from NOS. By clearing excess superoxide, SOD and CAT restored normal reactivity. There is evidence that reactive oxygen species diminish NO bioactivity in human diseases including systemic hypertension (20). Our data indicate a potential role in pulmonary hypertension associated with congenital heart disease as well. Further studies can be focused on determining vascular NO production, potential sources of excess vascular superoxide production, and the interactions between these as potential mechanisms of early endothelial dysfunction in this model of pulmonary hypertension.
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ACKNOWLEDGEMENTS |
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The technical assistance of Daniel Swartz, Elliott Rosenkrantz, and Michael J. Johengen is gratefully acknowledged.
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FOOTNOTES |
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This work was supported by the National Heart, Lung, and Blood Institute Grants HL-54705 (R. H. Steinhorn), HL-60190 (S. M. Black), and HL-61284 (J. R. Fineman).
Address for reprint requests and other correspondence: R. H. Steinhorn, Neonatology, Children's Memorial Hospital, 2300 Children's Plaza #45, Chicago, IL 60614 (E-mail: r-steinhorn{at}northwestern.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 12 June 2000; accepted in final form 14 August 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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B. Ovadia, O. Reinhartz, R. Fitzgerald, J. M. Bekker, M. J. Johengen, A. Azakie, S. Thelitz, S. M. Black, and J. R. Fineman Alterations in ET-1, not nitric oxide, in 1-week-old lambs with increased pulmonary blood flow Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H480 - H490. [Abstract] [Full Text] [PDF]
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 B. Thebaud, T. Petit, P. de Lagausie, J. Dall'Ava-Santucci, J.-C. Mercier, and A. T. Dinh-Xuan Altered Guanylyl-Cyclase Activity In Vitro of Pulmonary Arteries from Fetal Lambs with Congenital Diaphragmatic Hernia Am. J. Respir. Cell Mol. Biol., July 1, 2002; 27(1): 42 - 47. [Abstract] [Full Text] [PDF]
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 T.-F. Chou, M.-S. Wu, C.-T. Chien, C.-C. Yu, and C.-F. Chen Enhanced expression of nitric oxide synthase in the early stage after increased pulmonary blood flow in rats Eur. J. Cardiothorac. Surg., February 1, 2002; 21(2): 331 - 336. [Abstract] [Full Text] [PDF]
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M. Medhora, M. Bousamra II, D. Zhu, L. Somberg, and E. R. Jacobs Upregulation of collagens detected by gene array in a model of flow-induced pulmonary vascular remodeling Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H414 - H422. [Abstract] [Full Text] [PDF]
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