The pathophysiological basis of chronic hypoxic pulmonary hypertension in the mouse: vasoconstrictor and structural mechanisms contribute equally.

Chronic hypoxic pulmonary hypertension is characterized by a sustained increase in pulmonary arterial pressure due to abnormally elevated pulmonary vascular resistance. This increased vascular resistance was previously thought to be due largely to changes in the structure of the pulmonary vasculature, i.e. lumen narrowing due to wall hypertrophy and loss of vessels. Recently, this model has been challenged by the demonstration that hypoxic pulmonary hypertension in the rat is caused almost completely by sustained vasoconstriction. The contribution of this vasocontriction to hypoxic pulmonary hypertension has not been examined directly in other species. We exposed groups of mice to hypoxia (10% O(2)) or normoxia for 3 weeks, following which the lungs were removed post mortem, and vascular resistance was measured in an isolated, ventilated, perfused preparation. Mean pulmonary vascular resistance was significantly increased in hypoxic compared with control normoxic lungs. The rho kinase inhibitor Y27635 (10(-4)m) (Tocris Bioscience, Bristol, United Kingdom.) significantly reduced the mean (± SEM) hypoxia induced increase by 45.4 (10.8)%, implying that structural vascular changes acounted for the remainder of the hypoxic increase. Stereological quantification showed a significant reduction in the mean lumen diameter of the fully relaxed vessels in hypoxic lungs compared with normoxic control lungs; there was no intra-acinar vessel loss. Thus, in contrast to the rat, hypoxic pulmonary hypertension in the mouse is due to two mechanisms contributing equally: sustained vasoconstriction and structural lumen narrowing of intra-acinar vessels. These important species diferences must be considered when using genetically mutated mice to investigate the mechanisms underlying pulmonary hypertension.

The α and Δ isoforms of CREB1 are required to maintain normal pulmonary vascular resistance.

Chronic hypoxia causes pulmonary hypertension associated with structural alterations in pulmonary vessels and sustained vasoconstriction. The transcriptional mechanisms responsible for these distinctive changes are unclear. We have previously reported that CREB1 is activated in the lung in response to alveolar hypoxia but not in other organs. To directly investigate the role of α and Δ isoforms of CREB1 in the regulation of pulmonary vascular resistance we examined the responses of mice in which these isoforms of CREB1 had been inactivated by gene mutation, leaving only the ß isoform intact (CREB(αΔ) mice). Here we report that expression of CREB regulated genes was altered in the lungs of CREB(αΔ) mice. CREB(αΔ) mice had greater pulmonary vascular resistance than wild types, both basally in normoxia and following exposure to hypoxic conditions for three weeks. There was no difference in rho kinase mediated vasoconstriction between CREB(αΔ) and wild type mice. Stereological analysis of pulmonary vascular structure showed characteristic wall thickening and lumen reduction in hypoxic wild-type mice, with similar changes observed in CREB(αΔ). CREB(αΔ) mice had larger lungs with reduced epithelial surface density suggesting increased pulmonary compliance. These findings show that α and Δ isoforms of CREB1 regulate homeostatic gene expression in the lung and that normal activity of these isoforms is essential to maintain low pulmonary vascular resistance in both normoxic and hypoxic conditions and to maintain the normal alveolar structure. Interventions that enhance the actions of α and Δ isoforms of CREB1 warrant further investigation in hypoxic lung diseases.