Transgenic Gtpch Deficiency and Overexpression in Mouse

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Using murine models with deficient BH4 biosynthesis, complemented by targeted transgenic animals with increased endothelial BH4 biosynthesis, we have revealed that BH4 plays a pivotal role in eNOS function and regulation of the pulmonary circulation (Figure 4).

We first demonstrate that congenital BH4 deficiency in the hph-1 mouse results in the development of pulmonary hypertension and vascular remodelling in the adult under normoxic conditions and exacerbates the response to hypoxia [43]. Conversely, augmentation of endothelial BH4 biosynthesis in the GCH transgenic mouse (in which GCH-overexpression is target to endothelial cells) protects against the development of hypoxia-induced pulmonary hypertension and vascular remodelling during 4 weeks of hypoxia (unpublished data). Selective restoration of endothelial BH4 levels in the hph1 strain by intercross with the GCH transgenic mouse rescues the effects of systemic BH4 deficiency. A striking quantitative correlation was observed between lung BH4 levels and the development of pulmonary hypertension across the 5 genetic mouse models evaluated in our studies, suggesting that BH4 bioavailability controls both pulmonary vascular tone and structural remodelling in a dose-dependent manner [43]. Significantly, our data show

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Figure 4. Schematic illustration of different parameters across the 5 genetic mouse models in our study. Gradual increase in BH4 levels, NO, eNOS activity and decrease in superoxide levels, across the genetic models, protect the pulmonary circulation (hphl is a transgenic GTPCH deficient mice model ; hph+/- is hphl heterozygous; GCH is a transgenic model of targeted-endothelial overexpression of GTPCH; GCH/hphl is the cross breeding strain of hphl and GCH.

Figure 4. Schematic illustration of different parameters across the 5 genetic mouse models in our study. Gradual increase in BH4 levels, NO, eNOS activity and decrease in superoxide levels, across the genetic models, protect the pulmonary circulation (hphl is a transgenic GTPCH deficient mice model ; hph+/- is hphl heterozygous; GCH is a transgenic model of targeted-endothelial overexpression of GTPCH; GCH/hphl is the cross breeding strain of hphl and GCH.

that BH4 deficiency is associated with increased superoxide production, evidence of uncoupled NOS activity.

Our findings of pulmonary hypertension in normoxic hph-1 mice have been confirmed by independent investigators [60]. The elevated right ventricular systolic pressure in the BH4-deficient hph-1 mice is at least comparable to that previously observed in mice deficient in eNOS (eNOS- KO), with both strains showing exacerbated responses to chronic hypoxia [19,72,73]. However, vascular remodelling, a hallmark of pulmonary hypertension, was not seen in lungs from eNOS-KO mice kept in a normal oxygen atmosphere [72,93], whereas vascular remodelling was clearly evident in both hph-1 heterozygotes and homozygotes compared with wild-type littermates under normal oxygen conditions. This discordance in the severity of the phenotype between genetic eNOS deficiency and eNOS dysfunction resulting from genetic BH4 deficiency suggests that loss of NO production alone is not the sole mediator of the vascular pathology. Rather, our findings highlight the importance of increased eNOS-dependent superoxide production in playing a pathogenic role in both vascular remodelling and pulmonary hypertension.

Indeed, vascular superoxide production has a number of potentially important effects in the vascular wall, including effects on NO signalling through scavenging and peroxynitrite generation and through modulation of redox-sensitive signalling pathways [9]. Superoxide has been shown to influence proliferation and apoptosis of pulmonary vascular smooth muscle cells [85]. Our findings highlight the importance of endothelial BH4 availability as a reciprocal modulator of both NO and superoxide production by eNOS and provides a mechanistic link between previous observations of increased NOS protein levels and reduced NO bioactivity [20,48]. While chronic hypoxia increases eNOS expression in wild-type mice, BH4 levels remained unchanged, thereby leading to a relative BH4 deficiency [43]. Targeting NOS regulation and enzymatic coupling, rather than eNOS protein levels or total enzymatic activity, may be a more promising therapeutic strategy in pulmonary hypertension.

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