AMPK deficiency in smooth muscles causes persistent pulmonary hypertension of the new-born and premature death.

AMPK has been reported to facilitate hypoxic pulmonary vasoconstriction but, paradoxically, its deficiency precipitates pulmonary hypertension. Here we show that AMPK-α1/α2 deficiency in smooth muscles promotes persistent pulmonary hypertension of the new-born. Accordingly, dual AMPK-α1/α2 deletion in smooth muscles causes premature death of mice after birth, associated with increased muscularisation and remodeling throughout the pulmonary arterial tree, reduced alveolar numbers and alveolar membrane thickening, but with no oedema. Spectral Doppler ultrasound indicates pulmonary hypertension and attenuated hypoxic pulmonary vasoconstriction. Age-dependent right ventricular pressure elevation, dilation and reduced cardiac output was also evident. KV1.5 potassium currents of pulmonary arterial myocytes were markedly smaller under normoxia, which is known to facilitate pulmonary hypertension. Mitochondrial fragmentation and reactive oxygen species accumulation was also evident. Importantly, there was no evidence of systemic vasculopathy or hypertension in these mice. Moreover, hypoxic pulmonary vasoconstriction was attenuated by AMPK-α1 or AMPK-α2 deletion without triggering pulmonary hypertension.

Hypoxic pulmonary vasoconstriction--invited article.

Hypoxic pulmonary vasoconstriction (HPV) is an adaptive mechanism that in the face of localised alveolar hypoxia diverts blood away from poorly ventilated regions of the lung, thereby preserving ventilation/perfusion matching. HPV has been recognised for many years, but although the underlying mechanisms are known to reside within the arteries themselves, their precise nature remains unclear. There is a growing consensus that mitochondria act as the oxygen sensor, and that Ca(2+) release from ryanodine-sensitive stores and Rho kinase-mediated Ca(2+) sensitisation are critical for sustained vasoconstriction, though Ca(2+) entry via both voltage-dependent and/or -independent pathways has also been implicated. There is, however, controversy regarding the signalling pathways that link the oxygen sensor to its effectors, with three main hypotheses. The AMP-activated protein kinase (AMPK) hypothesis proposes that hypoxic inhibition of mitochondrial function increases the AMP/ATP ratio and thus activates AMPK, which in turn mediates cADPR-dependent mobilisation of ryanodine-sensitive sarcoplasmic reticulum Ca(2+) stores. In contrast the two other hypotheses invoke redox signalling, albeit in mutually incompatible ways. The Redox hypothesis proposes that hypoxia suppresses mitochondrial generation of reactive oxygen species (ROS) and causes the cytosol to become more reduced, with subsequent inhibition of K(V) channels, depolarisation and voltage-dependent Ca(2+) entry. In direct contrast the ROS hypothesis proposes that hypoxia causes an apparently paradoxical increase in mitochondrial ROS generation, and it is this increase in ROS that acts as the signalling moiety. In this article we describe our current understanding of HPV, and evidence in support of these models of oxygen-sensing.