Adverse events during the perinatal period are associated with an increased risk to develop cardiometabolic diseases later in life. We established a murine model to study long-term effects of perinatal hypoxia (PH) on the pulmonary circulation. We previously demonstrated that PH led to an impaired regulation of pulmonary vascular tone in adulthood, linked to alterations in K+ channels in males and in the nitric oxide (NO)/cyclic guanosine monophosphate pathway in females. Moreover, simultaneous administration of inhaled NO (iNO) during PH exposure prevented adverse effects of PH on adult pulmonary vasculature in females. The present study showed that PH induced a significant increase in right ventricular pressure in males and females, and an enhanced sensitivity to acute hypoxia in females. PH significantly reduced acetylcholine-induced relaxation in pulmonary artery, to a greater extent in females than in males. PH led to right ventricular hypertrophy in adulthood, appearing earlier in males than in females. Morphometric measurements showed a significant increase in the number of 25-75-µm pulmonary vessels in male lungs following PH, probably resulting in increased pulmonary vascular resistance. The effects of prolonged hypoxia in adulthood differed between males and females. Perinatal iNO during PH prevented PH-induced alterations in the cardiopulmonary system, whereas perinatal iNO alone could have some adverse effects. Therefore, PH led to long-lasting alterations in the regulation of adult pulmonary circulation, which vary between males and females. In males, the increased pulmonary vascular resistance was associated with morphological changes besides functional alterations, whereas females showed an important pulmonary vascular dysfunction. Keywords: Perinatal hypoxia, Pulmonary circulation, Endothelium-dependent relaxation, Phosphodiesterases, Sex differences.

• MeSH
• Pulmonary Artery metabolism   physiopathology   drug effects   MeSH
• Vascular Resistance physiology   MeSH
• Hypoxia * physiopathology   metabolism   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Animals, Newborn MeSH
• Nitric Oxide metabolism   MeSH
• Pulmonary Circulation * physiology   MeSH
• Sex Characteristics MeSH
• Sex Factors MeSH
• Pregnancy MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Nitric Oxide MeSH

Activators of hypoxia inducible factors (HIFs), such as roxadustat, are promising agents for anemia treatment. However, since HIFs are also involved in the regulation of the pulmonary circulation, we hypothesized that roxadustat increases pulmonary vascular resistance and vasoconstrictor reactivity. Using isolated, cell-free solution perfused rat lungs, we found perfusion pressure-flow curves to be shifted to higher pressures by 2 weeks of roxadustat treatment (10 mg/kg every other day), although not as much as by chronic hypoxic exposure. Vasoconstrictor reactivity to angiotensin II and acute hypoxic challenges was not altered by roxadustat. Since roxadustat may inhibit angiotensin-converting enzyme 2 (ACE2), we also tested a purported ACE2 activator, diminazene aceturate (DIZE, 0.1 mM). It produced paradoxical, unexplained pulmonary vasoconstriction. We conclude that the risk of serious pulmonary hypertension is not high when roxadustat is given for 14 days, but monitoring is advisable.

• MeSH
• Angiotensin-Converting Enzyme 2 * MeSH
• Vascular Resistance MeSH
• Hypoxia chemically induced   MeSH
• Rats MeSH
• Vasoconstrictor Agents * pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Angiotensin-Converting Enzyme 2 * MeSH
• Vasoconstrictor Agents * MeSH

The development of hypoxic pulmonary hypertension is characterized by the structural remodeling of pulmonary arteries. However, the relationship between changes of arterial cells and the extracellular matrix remains unclear. We focused on the evaluation of the non-fibrillar collagen changes in tunica media induced by a four-day exposure to hypoxia and the correlation of these changes with the pulmonary arterial wall structure modifications. We used 20 adult male Wistar rats. The amount and localization of collagen VI, collagen IV, matrix metalloproteinase (MMP) 2, and MMP9 were tested in pulmonary arteries immunohistochemically. Two-dimensional electrophoresis and messenger RNA (mRNA) expression were used for the subsequent comparison of protein changes in arterial tunica media cells (normoxia/hypoxia). Collagen VI was significantly reduced strictly in the tunica media of conduit arteries of hypoxia-exposed rats; however, its mRNA increased. The amount of collagen IV and its mRNA were not altered. We detected a significant increase of MMP9 strictly in the tunica media. In addition, a significantly increased number of MMP9-positive cells surrounded the arteries. MMP2 and the expression of its mRNA were decreased in tunica media. We conclude that the loss of collagen VI is an important step characterizing the remodeling of pulmonary arteries. It could influence the phenotypic status and behavior of smooth muscle cells and modify their proliferation and migration.

• Keywords
• collagen VI, hypoxic pulmonary hypertension, pulmonary arterial remodeling, smooth muscle cells, tunica media,
• Publication type
• Journal Article MeSH