We read with great interest the recent manuscript by BOUVARD et al. [1], which suggested the gap junctional protein connexin-43 (Cx43) to be a promising target for the treatment of chronic hypoxic pulmonary hypertension (CHPH). Therein, the authors demonstrated increased Cx43 expression in human pulmonary arteries of CHPH patients, while heterozygous Cx43 deficient mice were partially protected from CHPH.These findings align with a series of previous studies highlighting the role of connexins in the pulmonary vascular response to hypoxia: I. McMurtry and co-workers first reported that the non-specific gap junction blocker 18α-glycyrrhetinic acid blunts the acute vasoconstrictive response to hypoxia in isolated perfused rat lungs [2]. Using a combination of small peptide inhibitors and gene deficient mice, subsequent work by our own groups demonstrated that both connexin-40 (Cx40) and Cx43 contribute additively to hypoxic pulmonary vasoconstriction, and that Cx40 deficient mice are largely protected from the development of CHPH [3]. Attenuation of the vasoconstrictive response of pulmonary arteries to hypoxia in vivo and ex vivo by 18α-glycyrrhetinic acid was further confirmed by the laboratory of J.P.T. Ward and P.I. Aaronson [4]. Consistent with these reports, the findings by BOUVARD et al.[1] consolidate the requirement of connexins for the pulmonary vascular response to hypoxia. Notably, however, this concept has recently been challenged by a report that Cx40 deficient mice develop more severe CHPH, which can be attenuated by adenoviral Cx40 overexpression [5]. The reason for the obvious discrepancy between these [5] and earlier [3] findings remains unclear.Connexins are the building blocks of gap junctions, i.e. they form intercellular communication "channels" composed of two opposing homo-or heterotypic (i.e. identical or not) connexons, each of which is again a hexamer consisting of six identical (homomeric) or different (heteromeric) connexins [6]. In the vasculature, gap junctions are typically composed of one of three connexins, namely connexins 37, 40 and 43 [6]. In the systemic circulation, vascular gap junctions have been long recognised as important "highways" for retrograde signal conduction from capillaries to upstream arterioles in order to match resistance vessel tone and, thus, blood flow to local demands in the "downstream" tissue. In the lung, an analogous signal propagation from capillaries to upstream arterioles mediates the pulmonary vascular response to hypoxia. This signal conduction is required due to the spatial separation between the site of gas exchange, i.e. the alveolo-capillary compartment, and the site of vasoconstriction and vascular remodelling in response to acute and chronic hypoxia, respectively, which are localised in upstream arterioles [3,7]. Although direct visualisation of gas exchange in intact lungs by multispectral oximetry has revealed relevant precapillary oxygenation, indicating that alveolar hypoxia can directly impact oxygen tension (PO 2 ) in the vascular wall o...
