scholarly journals Chronic intrauterine pulmonary hypertension increases main pulmonary artery stiffness and adventitial remodeling in fetal sheep

2014 ◽  
Vol 307 (11) ◽  
pp. L822-L828 ◽  
Author(s):  
R. Blair Dodson ◽  
Matthew R. Morgan ◽  
Csaba Galambos ◽  
Kendall S. Hunter ◽  
Steven H. Abman
Keyword(s):  
Pulmonary Hypertension ◽  
Main Pulmonary Artery ◽  
Pulmonary Arteries ◽  
Clinical Syndrome ◽  
Late Gestation ◽  
Biaxial Testing ◽  
Mechanical Stiffness ◽  
Sheep Model ◽  
Fetal Sheep ◽  
Ecm Remodeling

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome that is characterized by high pulmonary vascular resistance due to changes in lung vascular growth, structure, and tone. PPHN has been primarily considered as a disease of the small pulmonary arteries (PA), but proximal vascular stiffness has been shown to be an important predictor of morbidity and mortality in other diseases associated with pulmonary hypertension (PH). The objective of this study is to characterize main PA (MPA) stiffness in experimental PPHN and to determine the relationship of altered biomechanics of the MPA with changes in extracellular matrix (ECM) content and orientation of collagen and elastin fibers. MPAs were isolated from control and PPHN fetal sheep model and were tested by planar biaxial testing to measure stiffness in circumferential and axial vessel orientations. Test specimens were fixed for histological assessments of the vascular wall ECM constituents collagen and elastin. MPAs from PPHN sheep had increased mechanical stiffness ( P < 0.05) and altered ECM remodeling compared with control MPA. A constitutive mathematical model and histology demonstrated that PPHN vessels have a smaller contribution of elastin and a greater role for collagen fiber engagement compared with the control arteries. We conclude that exposure to chronic hemodynamic stress in late-gestation fetal sheep increases proximal PA stiffness and alters ECM remodeling. We speculate that proximal PA stiffness further contributes to increased right ventricular impedance in experimental PPHN, which contributes to abnormal transition of the pulmonary circulation at birth.

scholarly journals Serotonin contributes to high pulmonary vascular tone in a sheep model of persistent pulmonary hypertension of the newborn

2013 ◽  
Vol 304 (12) ◽  
pp. L894-L901 ◽  
Author(s):  
Cassidy Delaney ◽  
Jason Gien ◽  
Gates Roe ◽  
Nicole Isenberg ◽  
Jenai Kailey ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Tryptophan Hydroxylase ◽  
Late Gestation ◽  
Persistent Pulmonary Hypertension ◽  
Sheep Model ◽  
Pulmonary Hemodynamics ◽  
Fetal Sheep ◽  
Pulmonary Arterial

Although past studies demonstrate that altered serotonin (5-HT) signaling is present in adults with idiopathic pulmonary arterial hypertension, whether serotonin contributes to the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN) is unknown. We hypothesized that 5-HT contributes to increased pulmonary vascular resistance (PVR) in a sheep model of PPHN and that selective 5-HT reuptake inhibitor (SSRI) treatment increases PVR in this model. We studied the hemodynamic effects of 5-HT, ketanserin (5-HT2A receptor antagonist), and sertraline, an SSRI, on pulmonary hemodynamics of the late gestation fetal sheep with PPHN caused by prolonged constriction of the ductus arteriosis. Brief intrapulmonary infusions of 5-HT increased PVR from 1.0 ± 0.07 (baseline) to 1.4 ± 0.22 mmHg/ml per minute of treatment ( P < 0.05). Ketanserin decreased PVR from 1.1 ± 0.15 (baseline) to 0.82 ± 0.09 mmHg/ml per minute of treatment ( P < 0.05). Sertraline increased PVR from 1.1 ± 0.17 (baseline) to 1.4 ± 0.17 mmHg/ml per minute of treatment ( P = 0.01). In addition, we studied 5-HT production and activity in vitro in experimental PPHN. Compared with controls, pulmonary artery endothelial cells from fetal sheep with PPHN exhibited increased expression of tryptophan hydroxylase 1 and 5-HT production by twofold and 56%, respectively. Compared with controls, 5-HT2A R expression was increased in lung homogenates and pulmonary artery smooth muscle cell lysates by 35% and 32%, respectively. We concluded that increased 5-HT contributes to high PVR in experimental PPHN through activation of the 5-HT2A receptor and that SSRI infusion further increases PVR in this model.

Altered endothelium-dependent responses in lambs with pulmonary hypertension and increased pulmonary blood flow

1996 ◽  
Vol 271 (2) ◽  
pp. H562-H570 ◽  
Author(s):  
V. M. Reddy ◽  
J. Wong ◽  
J. R. Liddicoat ◽  
M. Johengen ◽  
R. Chang ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Endothelial Function ◽  
Pulmonary Blood Flow ◽  
Main Pulmonary Artery ◽  
Plasma Concentrations ◽  
Phosphodiesterase Inhibitor ◽  
No Synthase ◽  
Late Gestation ◽  
Fetal Sheep

To investigate early endothelial function associated with increased pulmonary blood flow, vascular shunts were placed between the ascending aorta and main pulmonary artery in 18 late-gestation fetal sheep. Four weeks after delivery, the lambs were instrumented to measure vascular pressures and blood flows, and blood was collected to measure plasma concentrations of guanosine 3',5'-cyclic monophosphate [cGMP, the second messenger to nitric oxide (NO)-mediated vasodilation] and L-arginine (the precursor for NO synthesis). The responses to the endothelium-dependent vasodilators acetylcholine (ACh, 1.0 microgram/kg) and ATP (0.1 mg.kg-1.min-1), the endothelium-independent vasodilators M & B-22948 (a cGMP-specific phosphodiesterase inhibitor, 2.5 mg/kg) and inhaled NO (40 ppm), and N omega-nitro-L-arginine (an inhibitor of NO synthase, 5 mg/kg) were then compared with responses in 12 age-matched controls. Vasodilator responses in control lambs were determined during pulmonary hypertension induced by U-46619 (a thromboxane A2 mimic). Shunted lambs displayed a selective impairment of endothelium-dependent pulmonary vasodilation, an augmented pulmonary vasoconstricting response to NO synthase inhibition, increased plasma cGMP concentrations, and decreased L-arginine concentrations. Taken together, these data suggest that lambs with pulmonary hypertension and increased pulmonary blood flow have early aberrations in endothelial function, as manifested by increased basal NO activity, that cannot be further increased by agonist-induced endothelium-dependent vasodilators.

rhVEGF treatment preserves pulmonary vascular reactivity and structure in an experimental model of pulmonary hypertension in fetal sheep

2005 ◽  
Vol 289 (2) ◽  
pp. L315-L321 ◽  
Author(s):  
Theresa R. Grover ◽  
Thomas A. Parker ◽  
Neil E. Markham ◽  
Steven H. Abman
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Experimental Model ◽  
Vascular Remodeling ◽  
Ductus Arteriosus ◽  
Main Pulmonary Artery ◽  
Left Lung ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Pulmonary Vascular Remodeling

We have previously shown that lung VEGF expression is decreased in a fetal lamb model of PPHN and that VEGF165 inhibition causes severe pulmonary hypertension in fetal lambs. Therefore, we hypothesized that treatment with rhVEGF165 would preserve endothelium-dependent vasodilation and reduce the severity of pulmonary vascular remodeling in an experimental model of PPHN. We studied the effects of daily intrapulmonary infusions of rhVEGF after partial ligation of the ductus arteriosus (DA). We performed surgery in 24 late-gestation fetal lambs and placed catheters in the main pulmonary artery, left atrium, and aorta for pressure measurements and in the left pulmonary artery for drug infusions. A pressure transducer was placed around the LPA to measure blood flow to the left lung (Qp), and the DA was surgically constricted to induce pulmonary hypertension. rhVEGF165 or vehicle was infused for 7 or 14 days. ACh or 8-BrcGMP was infused on days 2 and 13 to assess endothelium-dependent and -independent vasodilation, respectively. ACh-induced vasodilation was reduced in PPHN lambs after 14 days (change in Qp from baseline, 106% vs. 11%). In contrast, the response to ACh was preserved in lambs treated with rhVEGF (change in Qp, 94% vs. 90%). Pulmonary vasodilation to 8-BrcGMP was not altered in PPHN lambs or enhanced by VEGF treatment. rhVEGF treatment increased expression of lung eNOS protein and decreased pulmonary artery wall thickness by 34% vs. PPHN lambs. We conclude that VEGF165 preserves endothelium-dependent vasodilation, upregulates eNOS expression, and reduces the severity of pulmonary vascular remodeling in experimental PPHN.

Endothelin-1 vasoactive responses in lambs with pulmonary hypertension and increased pulmonary blood flow

1995 ◽  
Vol 269 (6) ◽  
pp. H1965-H1972 ◽  
Author(s):  
J. Wong ◽  
V. M. Reddy ◽  
K. Hendricks-Munoz ◽  
J. R. Liddicoat ◽  
R. Gerrets ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Blood Flow ◽  
Heart Diseases ◽  
Main Pulmonary Artery ◽  
Similar Degree ◽  
Fetal Sheep ◽  
Endothelin 1

Increased concentrations of endothelin-1 (ET-1) are found in children with congenital heart diseases that produce increased pulmonary blood flow and pulmonary hypertension, but the role of ET-1 in the pathophysiology of pulmonary hypertension is unclear. Therefore, we investigated ET-1-induced vasoactive responses and ET-1 concentrations in an animal model of pulmonary hypertension and increased pulmonary blood flow. Vascular shunts were placed between the ascending aorta and main pulmonary artery in seven late-gestation fetal sheep. Four weeks after spontaneous delivery, ET-1 increased pulmonary vascular resistance by 29.7 +/- 34.4% (P < 0.05), the ETb-receptor agonist [Ala1,3,11,15]ET-1 (4AlaET-1) had no effect, and the ETa-receptor antagonist cyclo(D-Asp-L-Pro-D-Val-L-Leu-D-Trp) (BQ-123) decreased pulmonary vascular resistance by -16.0 +/- 5.6% (P < 0.05). In contrast, in six control lambs with a similar degree of pulmonary hypertension induced by U-46619, ET-1 and 4AlaET-1 decreased pulmonary vascular resistance by 24.8 +/- 17.6, and 20.0 +/- 13.8%, respectively (P < 0.05). In addition, systemic arterial concentrations of immunoreactive ET-1 were elevated in lambs with pulmonary hypertension (29.2 +/- 9.6 vs. 15.2 +/- 10.7 pg/ml, P < 0.05). Pulmonary hypertension and increased pulmonary blood flow alters the response of ET-1 from pulmonary vasodilation to vasoconstriction. These altered responses suggest a role for ET-1 and its receptors in the pathogenesis of pulmonary hypertension secondary to increased pulmonary blood flow.

Disruption of cGMP production in pulmonary arteries isolated from fetal lambs with pulmonary hypertension

1995 ◽  
Vol 268 (4) ◽  
pp. H1483-H1489 ◽  
Author(s):  
R. H. Steinhorn ◽  
J. A. Russell ◽  
F. C. Morin
Keyword(s):  
Pulmonary Hypertension ◽  
Soluble Guanylate Cyclase ◽  
Ductus Arteriosus ◽  
Pulmonary Veins ◽  
Pulmonary Arteries ◽  
Fourth Generation ◽  
Response Curves ◽  
Fetal Sheep ◽  
A 23187 ◽  
Arteries And Veins

Ligation of the ductus arteriosus of the fetal sheep produces severe pulmonary hypertension at birth. Standard tissue bath techniques were used to study third- and fourth-generation pulmonary arteries and veins isolated from fetal sheep with pulmonary hypertension created by ligation of the ductus arteriosus 11–12 days before birth as well as from age-matched control sheep. Vessels pretreated with indomethacin and propranolol were submaximally preconstricted with norepinephrine before exposure to A-23187 (10(-8) to 3 x 10(-7) M), sodium nitroprusside (SNP; 10(-9) to 10(-5) M), and nitric oxide (NO) gas (1-973 ppm). Pulmonary veins in both control and ligated animals relaxed similarly and completely to A-23187, SNP, and NO. Control pulmonary arteries relaxed by 16 +/- 2% to A-23187 and relaxed completely to SNP and NO, with concentration-response curves shifted rightward of those observed in pulmonary veins. Pulmonary arteries from ligated animals did not relax at all to A-23187. SNP relaxations in ligated arteries were shifted rightward of control. Ligated arteries relaxed by only 11 +/- 5% to the highest dose of NO. However, control and ligated pulmonary arteries relaxed similarly to 8-bromoguanosine 3',5'-cyclic monophosphate (8-bromo-cGMP; 10(-5) to 10(-3) M) and atrial natriuretic peptide (10(-9) to 10(-7) M). These data are most simply explained by decreased arterial vascular smooth muscle sensitivity to NO at the level of soluble guanylate cyclase.

scholarly journals Intrauterine endotoxin-induced impairs pulmonary vascular function and right ventricular performance in infant rats and improvement with early vitamin D therapy

2015 ◽  
Vol 309 (12) ◽  
pp. L1438-L1446 ◽  
Author(s):  
Erica Mandell ◽  
Kyle N. Powers ◽  
Julie W. Harral ◽  
Gregory J. Seedorf ◽  
Kendall S. Hunter ◽  
...  
Keyword(s):  
Vitamin D ◽  
Right Ventricular ◽  
Vascular Function ◽  
Late Gestation ◽  
Stroke Work ◽  
Mechanical Stiffness ◽  
Ventricular Performance ◽  
Ecm Remodeling ◽  
Collagen Iii ◽  
Fetal Rats

High pulmonary vascular resistance (PVR), proximal pulmonary artery (PA) impedance, and right ventricular (RV) afterload due to remodeling contribute to the pathogenesis and severity of pulmonary hypertension (PH). Intra-amniotic exposure to endotoxin (ETX) causes sustained PH and high mortality in rat pups at birth, which are associated with impaired vascular growth and RV hypertrophy in survivors. Treatment of ETX-exposed pups with antenatal vitamin D (vit D) improves survival and lung growth, but the effects of ETX exposure on RV-PA coupling in the neonatal lung are unknown. We hypothesized that intrauterine ETX impairs RV-PA coupling through sustained abnormalities of PA stiffening and RV performance that are attenuated with vit D therapy. Fetal rats were exposed to intra-amniotic injections of ETX, ETX+vit D, or saline at 20 days gestation (term = 22 days). At postnatal day 14, pups had pressure-volume measurements of the RV and isolated proximal PA, respectively. Lung homogenates were assayed for extracellular matrix (ECM) composition by Western blot. We found that ETX lungs contain decreased α-elastin, lysyl oxidase, collagen I, and collagen III proteins ( P < 0.05) compared control and ETX+vit D lungs. ETX-exposed animals have increased RV mechanical stroke work ( P < 0.05 vs. control and ETX+vit D) and elastic potential energy ( P < 0.05 vs. control and ETX+vit D). Mechanical stiffness and ECM remodeling are increased in the PA ( P < 0.05 vs. control and ETX+vit D). We conclude that intrauterine exposure of fetal rats to ETX during late gestation causes persistent impairment of RV-PA coupling throughout infancy that can be prevented with early vit D treatment.

scholarly journals Gestational long-term hypoxia induces metabolomic reprogramming and phenotypic transformations in fetal sheep pulmonary arteries

2021 ◽  
Author(s):  
Eric Leslie ◽  
Vanessa Lopez ◽  
Nana A.O. Anti ◽  
Rafael Alvarez ◽  
Isaac Kafeero ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arteries ◽  
Metabolic Reprogramming ◽  
Persistent Pulmonary Hypertension ◽  
Wall Thickening ◽  
Omega 3 ◽  
Alpha Linolenic Acid ◽  
Fetal Sheep ◽  
Functional Changes

Gestational long-term hypoxia increases the risk of myriad diseases in infants including persistent pulmonary hypertension. Similar to humans, fetal lamb lung development is susceptible to long-term intrauterine hypoxia, with structural and functional changes associated with the development of pulmonary hypertension including pulmonary arterial medial wall thickening and dysregulation of arterial reactivity, which culminates in decreased right ventricular output. To further explore the mechanisms associated with hypoxia-induced aberrations in the fetal sheep lung, we examined the premise that metabolomic changes and functional phenotypic transformations occur due to intrauterine, long-term hypoxia. To address this, we performed electron microscopy, Western immunoblotting, calcium imaging, and metabolomic analyses on pulmonary arteries isolated from near-term fetal lambs that had been exposed to low- or high-altitude (3801 m) hypoxia for the latter 110+ days of gestation. Our results demonstrate that the sarcoplasmic reticulum was swollen with high luminal width and distances to the plasma membrane in the hypoxic group. Hypoxic animals presented with higher endoplasmic reticulum stress and suppressed calcium storage. Metabolically, hypoxia was associated with lower levels of multiple omega-3 polyunsaturated fatty acids and derived lipid mediators (e.g. eicosapentanoic acid, docosahexaenoic acid, alpha-linolenic acid, 5-hydroxyeicosapentaenoic acid (5-HEPE), 12-HEPE, 15-HEPE, prostaglandin E3, and 19(20)-epoxydocosapentaenoic acid), and higher levels of some omega-6 metabolites (p<0.02) including 15-Keto prostaglandin E2 and linoleoylglycerol. Collectively, the results reveal broad evidence for long-term hypoxia-induced metabolic reprogramming and phenotypic transformations in the pulmonary arteries of fetal sheep, conditions that likely contribute to the development of persistent pulmonary hypertension.

FRI0196 INVOLVEMENT OF THE PULMONARY ARTERIES IN PATIENTS WITH TAKAYASU ARTERITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 681-682
Author(s):  
X. Kong ◽  
L. MA ◽  
P. LV ◽  
X. Cui ◽  
R. Chen ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Pulmonary Hypertension ◽  
Takayasu Arteritis ◽  
Main Pulmonary Artery ◽  
Pulmonary Arteries ◽  
Pulmonary Trunk ◽  
Cardiac Insufficiency ◽  
Multiple Imaging ◽  
Pet Ct ◽  
The Right

Background:Takayasu arteritis (TA) is a chronic, granulomatous large-vessel vasculitis. It involves the aorta and its main branches predominantly, and leads to vascular thickness, stenosis and occlusion [1]. Besides the aorta and its branches, pulmonary arteries (PAs) are involved in TA. PAs have been reported to be involved in 6.9% to 80% of TA patients from different populations [2-3].Objectives:We investigated the clinical characteristics, pulmonary parenchymal features and cardiac functions in TA patients with PA involvement by combining multiple imaging modalities (MRA, CTA, PET-CT, lung VQ scan, echocardiography and high-resolution computed tomography (HRCT)). Our aim was to elicit better understanding of TA patients with PA involvement to aid rational treatment for these patients and improve their prognosis.Methods:We enrolled 216 patients with TA from a large prospective cohort. PAI was assessed in each patient based on data from magnetic resonance angiography/computed tomography angiography. Pulmonary hypertension, cardiac function, and pulmonary parenchymal abnormalities were evaluated further in patients with PAI based on echocardiography, New York Heart Association Functional Classification and pulmonary computed tomography, respectively. These abnormalities related to PAI were followed up to evaluate treatment effects.Results:PAI was detected in 56/216 (25.93%) patients, which involved the pulmonary trunk, main PAs and small vessels in the lungs. Among patients with PAI, 28 (50%) patients were accompanied by pulmonary hypertension, which was graded as ‘severe’ in 9 (16.07%), ‘moderate’ in 10 (17.86%) and mild in 9 (16.07%). Forty (71.43%) patients had cardiac insufficiency (IV: 6, 10.71%; III: 20, 35.71%; II: 14, 25.00%). Furthermore, 21 (37.50%) patients presented with abnormal parenchymal features in the area corresponding to PAI (e.g., the mosaic sign, infarction, bronchiectasis). During follow-up, two patients died due to abrupt pulmonary thrombosis. In the remaining patients, the abnormalities mentioned above improved partially after routine treatment.Conclusion:PA involvement is very common in TA patients. Physicians should be alerted to PA involvement even if obvious pulmonary symptoms are absent because they can cause PH, cardiac insufficiency as well as pulmonary parenchymal lesions, which will worsen the prognosis.References:[1]M.L.F. Zaldivar Villon, J.A.L. de la Rocha, L.R. Espinoza. Takayasu Arteritis: Recent Developments. Curr Rheumatol Rep 2019; 21: 45.[2]N. Matsunaga, K. Hayashi, I. Sakamoto, et al. Takayasu arteritis: protean radiologic manifestations and diagnosis. Radiographics 1997; 17: 579-594.[3]M. Bicakcigil, K. Aksu, S. Kamali, et al. Takayasu’s arteritis in Turkey - clinical and angiographic features of 248 patients. Clin Exp Rheumatol 2009; 27: S59-64.Figure 1.Imaging of PA lesions in TA patientsA:Dilationof the pulmonary trunk; B: thickness of the pulmonary trunk; C: stenosis of the right main PA; D: embolism of lower PAs on both sides; E: inflammation of the pulmonary-trunk root upon PET–CT; F: absence of left PAs and stenosis of the right main PA; G–I: pulmonary MRA (G), CTA (H) and VQ scan (I) of a patient with TA. MRA shows a fine right main PA and low perfusion in the right lung (G); CTA demonstrates a fine right main PA and fewer PA branches in the right lung (H); lung VQ scan shows multiple arterial emboli in the right lung and obvious less blood supply to the right lung.Figure 2.Pulmonary lesions on HRCT.A: Themosaicsign in the left lung; B: Pulmonary infarction of the right middle lobe; C: Mild pleural effusion on the left side; D: Bronchiectasis in the right lung; E–F: Ground-glass opacity (E) in the right upper lobe of a TA patient with an embolism of the right upper pulmonary branches (F); G–I: Cavitation (G) and mass-like consolidation (H) in the patient with severe stenosis of right main pulmonary artery (I).Acknowledgments:NoneDisclosure of Interests:None declared

scholarly journals Skeletal muscle amino acid uptake is lower and alanine production is greater in late gestation intrauterine growth-restricted fetal sheep hindlimb

2019 ◽  
Vol 317 (5) ◽  
pp. R615-R629 ◽  
Author(s):  
Eileen I. Chang ◽  
Stephanie R. Wesolowski ◽  
Elizabeth A. Gilje ◽  
Peter R. Baker ◽  
Julie A. Reisz ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Protein ◽  
External Iliac Artery ◽  
Late Gestation ◽  
Acid Uptake ◽  
Sheep Model ◽  
Fetal Sheep ◽  
Biceps Femoris Muscle ◽  
Intrauterine Growth ◽  
Uptake Rates

In a sheep model of intrauterine growth restriction (IUGR) produced from placental insufficiency, late gestation fetuses had smaller skeletal muscle mass, myofiber area, and slower muscle protein accretion rates compared with normally growing fetuses. We hypothesized that IUGR fetal muscle develops adaptations that divert amino acids (AAs) from protein accretion and activate pathways that conserve substrates for other organs. We placed hindlimb arterial and venous catheters into late gestation IUGR ( n = 10) and control (CON, n = 8) fetal sheep and included an external iliac artery flow probe to measure hindlimb AA uptake rates. Arterial and venous plasma samples and biceps femoris muscle were analyzed by mass spectrometry-based metabolomics. IUGR fetuses had greater abundance of metabolites enriched within the alanine, aspartate, and glutamate metabolism pathway compared with CON. Net uptake rates of branched-chain AA (BCAA) were lower by 42%–73%, and muscle ammoniagenic AAs (alanine, glycine, and glutamine) were lower by 107%–158% in IUGR hindlimbs versus CON. AA uptake rates correlated with hindlimb weight; the smallest hindlimbs showed net release of ammoniagenic AAs. Gene expression levels indicated a decrease in BCAA catabolism in IUGR muscle. Plasma purines were lower and plasma uric acid was higher in IUGR versus CON, possibly a reflection of ATP conservation. We conclude that IUGR skeletal muscle has lower BCAA uptake and develops adaptations that divert AAs away from protein accretion into alternative pathways that sustain global energy production and nitrogen disposal in the form of ammoniagenic AAs for metabolism in other organs.

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