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Hypoxic vasoconstriction is a response that is seen in the pulmonary circulation but not in any other vascular bed in the body. By diverting blood flow away from less well-ventilated regions in the lung, it acts to match perfusion to ventilation and thus to optimize oxygen uptake and arterial PO2 . This is an advantage in many lung diseases that are heterogeneously distributed throughout the lung so that some regions are hypoxic while other areas remain disease free and well oxygenated. However, when alveolar hypoxia becomes very widespread, as occurs at high altitude or when lungdisease is diffusely spread throughout the lung, hypoxic vasoconstriction increases pulmonary vascular resistance and contributes to the development of pulmonary hypertension, right ventricular overload and, ultimately, right ventricular failure (Rowan, Keane, Gaine, &McLoughlin, 2016). Despite its importance, the mechanisms that mediate this response in vivo remain incompletely understood. In this issue of Experimental Physiology, Strielkov et al. (2018) report the results of a careful series of experiments in murine pulmonary arterial vessels isolated from different levels of the vascular tree, which have shown, for the first time, that hypoxic vasoconstriction is observed only in the small intrapulmonary vessels of the mouse lung and not in the larger intrapulmonary arteries or in the extrapulmonary pulmonary arteries. These findings fill an important gap in our knowledge and provide information that is essential for all future researchers who seek to take advantage of genetic manipulations in mice to elucidate themechanisms underlying this lung-specific response. Hypoxic pulmonary vasoconstriction is a property that is intrinsic to the pulmonary circulation and does not require extrinsic innervation of the lung or hormonal signalling from remote organs. Many different experimental approaches have been used to identify the cells within the lung that are involved in sensing hypoxia and the transduction mechanisms that link sensing to the vasoconstrictor response. These include isolated, ventilated, perfused lung preparations, isolated vessels and cells isolated from the lung. When isolated pulmonary vessel preparations were first developedusing larger extrapulmonarypulmonary arteries, therewas somedoubt aboutwhether or not theydisplayed thehypoxic vasoconstrictor response that was observed in the intact lung. A two-phase response to hypoxia was identified in these vessels, with an early constriction that reached a peak and relaxed within 10–15 min, followed by a second phase of sustained constriction that developed progressively over the subsequent 60–90min or longer (Sylvester, Shimoda, Aaronson, &Ward, 2012). An early transient constriction was also reported in isolated systemic arterial vessels, but the late-phase sustained contraction was seen only in pulmonary vessels. A slow-onset hypoxic constriction was also observed in the smaller intrapulmonary vessels of several species, similar to that seen in larger vessels (Sylvester et al., 2012). Thus, even though the time course of this later sustained contraction does not follow exactly the time course of hypoxic pulmonary vasoconstriction in vivo, it has been used extensively to investigate themechanisms underlying this phenomenon. The use of isolated vessels has allowed careful study of the separate roles of the smoothmuscle cells and endothelial cells and how local intercellular communication within the vessel wall contributes to this response. Given that hypoxic vasoconstriction could be examined in the larger extrapulmonary pulmonary arteries of several species and because of the relative ease with which they can be isolated, larger vessels are often used in such studies. It would have been tempting to presume that the same is the case in the mouse, particularly given the much greater difficulty of isolating smaller intrapulmonary vessels from the murine lung. However, Strielkov et al. (2018) carefully studied HPV in isolated murine vessels of three different sizes, extrapulmonary pulmonary arteries (500–700 μm in diameter), larger intrapulmonary arteries (450–650 μm in diameter) and small intrapulmonary arteries (80–200 μm in diameter) and found that sustained hypoxic contractionwas present only in the small intrapulmonary arteries. This has obvious implications for studies inwhichmurine vascular rings are used to examinehypoxic contraction.However, there are also important implications for studies inwhich isolatedprimarymurine cells are used to study the mechanisms of hypoxic contraction. The data of Strielkov et al. (2018) suggest that only smooth muscle and endothelial cells from intrapulmonary vessels as small as the ones they used (80–200μm indiameter) or smaller should be examined, because the largermurine vessels do not show this property. A further note of caution is sounded by the results of Strielkov et al. (2018). They used their carefully characterized small intrapulmonary artery preparation to examine the role of transient receptor potential channel 6 (TRPC6) in hypoxic pulmonary vasoconstriction and found that it was not altered in these isolated vessels from the TRPC6−/− mouse. This finding is particularly notable because this group previously reported that TRPC6 loss in mice abolished hypoxic pulmonary vasoconstriction in the intact lung (Weissmann et al., 2006), a finding that has been confirmed by others (Smith et al., 2015). Clearly, there are many possible explanations for this apparent discordance between intact lungs and isolated vessels. For example, differentmechanisms ofHPVmight operate at different levels within the vascular bed.Moreover, vessels of a size and from a location that canbeexamined in the isolatedvessel preparation (wiremyograph)might not be themajor site of increased resistance in response tohypoxia in the intact lung. Regardless of the exact reasons for the difference between intact lungs and isolated vessels, these results demonstrate that isolated vessels do not completely recapitulate hypoxic pulmonary vasoconstriction as it occurs in the intact lung and that multiple different experimental