Relating Genetics to Hypoxic Pulmonary Vascular Disease

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Studies in transgenic mice suggest that genetic factors might modulate the response to chronic hypoxia. For example, in the absence of hemoxygenase 1, there is reduced production of CO and its associated vasodilatory effects (54). PGI2 synthetase overexpression is protective against the hemodynamic and vascular changes of pulmonary hypertension. Serotonin has been implicated either in the increased vasoreactivity of the Fawn hooded rat and there is attenuated severity of disease in mice lacking the serotonin transporter gene or serotonin receptors (15, 19). We also showed that increased endogenous expression of serine elastase inhibitors will effectively reduce chronic hypoxia-induced pulmonary hypertension (56) as will exogenous administration of elastase inhibitors (28).

Figure 2. Lack of pulmonary vascular remodeling in Hiß*'' mice. Panels (A-E): Hart's elastin staining revealed the presence of vessels, located distally to the bronchi, at the level of alveoli and alveolar ducts, that contained only an IEL (or an IEL plus an incomplete EEL) (arrows) in lungs of normoxic (N) WT (A) and Hiß*'' mice (B). Lungs of hypoxic (H) WT mice showed the presence of thick-walled vessels containing both an IEL and a complete EEL (arrows; C and D), whereas no hypoxia-induced vascular remodeling occurred in Hiß*'' mice (arrows; E). F-J: SMC a-actin staining shows the presence of partially muscularized peripheral vessels (arrows) in lungs of normoxic WT (F) and Hiß*'' mice (G). Chronic hypoxia caused pulmonary vascular remodeling in WT mice, as revealed by the presence of fully muscularized vessels (arrows; H and I), but not in Hiß*'' mice (arrows, J). Bar = 50 um in all panels (Modified from Ref. 7).

Figure 2. Lack of pulmonary vascular remodeling in Hiß*'' mice. Panels (A-E): Hart's elastin staining revealed the presence of vessels, located distally to the bronchi, at the level of alveoli and alveolar ducts, that contained only an IEL (or an IEL plus an incomplete EEL) (arrows) in lungs of normoxic (N) WT (A) and Hiß*'' mice (B). Lungs of hypoxic (H) WT mice showed the presence of thick-walled vessels containing both an IEL and a complete EEL (arrows; C and D), whereas no hypoxia-induced vascular remodeling occurred in Hiß*'' mice (arrows; E). F-J: SMC a-actin staining shows the presence of partially muscularized peripheral vessels (arrows) in lungs of normoxic WT (F) and Hiß*'' mice (G). Chronic hypoxia caused pulmonary vascular remodeling in WT mice, as revealed by the presence of fully muscularized vessels (arrows; H and I), but not in Hiß*'' mice (arrows, J). Bar = 50 um in all panels (Modified from Ref. 7).

Both vascular endothelial growth factor (VEGF)-A and VEGF-B overexpressing mice show attenuation of chronic hypoxic pulmonary vascular disease (26). The protective mechanism of VEGF-B is unknown. Paradoxically, VEGF-B deficient mice, also show attenuation of chronic hypoxic pulmonary hypertension and pulmonary medial thickening (52). In VEGF-A overexpressing mice the protective mechanism is related to induction of nitric oxide synthase

(NOS). This is supported by the fact that in the NOS deficient mouse alveolar and associated vascular growth is impaired in hypoxia (4). Consistent with this, blockade of the VEGF receptor in newborn rat pups causes alveolar deficiency and pulmonary artery hypertrophy and pulmonary hypertension (24). In fact the combination of VEGF receptor blockade and hypoxia causes a very severe form of pulmonary hypertension and associated vascular changes (e.g., obliteration of small vessels in which there is evidence of intravascular endothelial cells) (44). The mechanism is thought to be related to apoptosis of endothelial cells and then the emergence ofa resistant population ofcells. In fact a caspase inhibitor which protects against apoptosis as well as with a bradykinin antagonist prevented these obliterative lesions whereas the pulmonary arterial medial hypertrophy persisted.

Carbon monoxide aggravates the effects of hypobaric hypoxia as reflected by an increase in the number of muscularized peripheral pulmonary arteries and in a more severe increase in pulmonary vascular resistance. Overexpression of hemoxygenase-1 protects mice against the inflammation and structural remodeling of chronic hypoxia (31). Heterozygous deletion of the transcription factor, hypoxia-inducible factor (HIF)-la, is associated with delayed development of polycythemia, right ventricular hypertrophy and pulmonary hypertension in chronically hypoxic rats (55). More recently the heterozygous deletion of the homologue, was shown to be associated with protection against pulmonary hypertension in association with suppression in endothelin-1 and plasma catecholamine levels (Fig. 2) (7).

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