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. 2010 Dec;299(6):R1676-84.
doi: 10.1152/ajpregu.00123.2010. Epub 2010 Sep 29.

Long-term exposure to high-altitude chronic hypoxia during gestation induces neonatal pulmonary hypertension at sea level

Emilio A Herrera  1 , Raquel A Riquelme, Germán Ebensperger, Roberto V Reyes, César E Ulloa, Gertrudis Cabello, Bernardo J Krause, Julian T Parer, Dino A Giussani, Aníbal J Llanos
Affiliations

Long-term exposure to high-altitude chronic hypoxia during gestation induces neonatal pulmonary hypertension at sea level

Emilio A Herrera et al. Am J Physiol Regul Integr Comp Physiol. 2010 Dec.

Abstract

We determined whether postnatal pulmonary hypertension induced by 70% of pregnancy at high altitude (HA) persists once the offspring return to sea level and investigated pulmonary vascular mechanisms operating under these circumstances. Pregnant ewes were divided into two groups: conception, pregnancy, and delivery at low altitude (580 m, LLL) and conception at low altitude, pregnancy at HA (3,600 m) from 30% of gestation until delivery, and return to lowland (LHL). Pulmonary arterial pressure (PAP) was measured in vivo. Vascular reactivity and morphometry were assessed in small pulmonary arteries (SPA). Protein expression of vascular mediators was determined. LHL lambs had higher basal PAP and a greater increment in PAP after N(G)-nitro-L-arginine methyl ester (20.9 ± 1.1 vs. 13.7 ± 0.5 mmHg; 39.9 ± 5.0 vs. 18.3 ± 1.3 mmHg, respectively). SPA from LHL had a greater maximal contraction to K(+) (1.34 ± 0.05 vs. 1.16 ± 0.05 N/m), higher sensitivity to endothelin-1 and nitroprusside, and persistence of dilatation following blockade of soluble guanylate cyclase. The heart ratio of the right ventricle-to-left ventricle plus septum was higher in the LHL relative to LLL. The muscle area of SPA (29.3 ± 2.9 vs. 21.1 ± 1.7%) and the protein expression of endothelial nitric oxide synthase (1.7 ± 0.1 vs. 1.1 ± 0.2), phosphodiesterase (1.4 ± 0.1 vs. 0.7 ± 0.1), and Ca(2+)-activated K(+) channel (0.76 ± 0.16 vs. 0.30 ± 0.01) were greater in LHL compared with LLL lambs. In contrast, LHL had decreased heme oxygenase-1 expression (0.82 ± 0.26 vs. 2.22 ± 0.44) and carbon monoxide production (all P < 0.05). Postnatal pulmonary hypertension induced by 70% of pregnancy at HA promotes cardiopulmonary remodeling that persists at sea level.

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Figures

Fig. 1.
Fig. 1.
Pulmonary arterial pressure (PAP) during the in vivo acute hypoxia protocol in lambs in the following 2 groups: conception, pregnancy, and delivery at low altitude (580 m) (LLL, ○) and conception at low altitude, pregnancy at high altitude (3,600 m) from 30% of gestation until delivery, and return to lowland (LHL, ●). Acute hypoxia was induced following a background infusion (gray bar) with 0.9% NaCl (A) or with the nitric oxide synthase (NOS) blockade inducer NG-nitro-l-arginine methyl ester (l-NAME, B). Values are means ± SE, calculated every minute during the experimental protocol. Significant differences (P < 0.05) are as follows: vs. preinfusion baseline (*), LHL vs. LLL (†), and l-NAME vs. 0.9% NaCl (‡).
Fig. 2.
Fig. 2.
Vasoconstrictor function of small pulmonary vessels isolated from LLL (○) and LHL (●) lambs. Values are the means ± SE for the vascular response to KCL (A) and to endothelin-1 (ET-1, B). Maximal response (Emax) and sensitivity (EC50 or pD2) were calculated (see text). Significant differences (P < 0.05) are as follows: LHL vs. LLL for Emax (†) and LHL vs. LLL for sensitivity (‡). Brackets denote concentration.
Fig. 3.
Fig. 3.
Vasodilator function of small pulmonary vessels isolated from LLL (○) and LHL (●) lambs. Values are the means ± SE for the vascular response to sodium nitroprusside (SNP, A) and to SNP in the presence of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10−5 M, B). Emax and sensitivity (EC50 or pD2) were calculated (see text). Significant differences (P < 0.05) are as follows: LHL vs. LLL for Emax (†) and LHL vs. LLL for sensitivity (‡).
Fig. 4.
Fig. 4.
mRNA expression of endothelial nitric oxide synthase (eNOS) in LLL (open bar) and LHL (filled bar) lambs. Values are the means ± SE for the mRNA expression of eNOS. Individual immunoblots are shown. Significant differences (P < 0.05) are LHL vs. LLL (†).
Fig. 5.
Fig. 5.
Components of the NO signaling pathway in LLL (open bars) and LHL (filled bars) lambs. Values are the means ± SE for the protein expression of eNOS (A), soluble guanylate cyclase (sGC, B), phosphodiesterase 5 (PDE5, C), and Ca2+-activated K+ channels (BKCa, D). E: individual immunoblots. Significant differences (P < 0.05) are LHL vs. LLL (†).
Fig. 6.
Fig. 6.
Components of the heme oxygenase (HO)-CO pathway in LLL (open bars) and LHL (filled bars) lambs. Values are means ± SE for the protein expression of HO-1 (A) and CO production by the pulmonary circulation (B). Individual immunoblots are shown (A). Significant differences (P < 0.05) are: LHL vs. LLL (†).
Fig. 7.
Fig. 7.
Representative micrograph of parenchymal pulmonary small arteries from LLL (A) and LHL (B) lams. van Giesson staining. PA, pulmonary artery. Bar: 100 μm. Magnification: ×40.
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