Hypoxic vasoconstriction of partial muscular intra-acinar pulmonary arteries in murine precision cut lung slices

Abstract

Background: Acute alveolar hypoxia causes pulmonary vasoconstriction (HPV) which serves to match lung perfusion to ventilation. The underlying mechanisms are not fully resolved yet. The major vascular segment contributing to HPV, the intra-acinar artery, is mostly located in that part of the lung that cannot be selectively reached by the presently available techniques, e.g. hemodynamic studies of isolated perfused lungs, recordings from dissected proximal arterial segments or analysis of subpleural vessels. The aim of the present study was to establish a model which allows the investigation of HPV and its underlying mechanisms in small intra-acinar arteries.

Videomorphometric Analysis of Hypoxic Pulmonary Vasoconstriction of Intra-pulmonary Arteries Using Murine Precision Cut Lung Slices

“…There is a relative broad consensus that hypoxia-evoked redox and ROS changes are essential for HPV and the development of pulmonary hypertension (reviewed in Sylvester et al 4 and Schumacker et al 5 ). Our own data support a central role of complex II of the mitochondrial respiratory chain in HPV 6,7 . Recently, Wang et al presented a completely new concept for oxygen sensing and HPV: Based on their data they propose that alveolar hypoxia is sensed by the adjacent capillaries causing membrane depolarization of the endothelial cells.…”

“…We have analyzed the oxygen partial pressure (pO 2 ) of medium pregassed with 1% O 2 , 5.3% CO 2 , 93.7% N 2 and with 21% O 2 , 5.3% CO 2 , 73.7% N 2 , respectively, using a blood gas analyzer. Immediately before feeding it into the perfusion chamber, the pO 2 of the hypoxic gassed MEM was 40 mmHg and that of the normoxic gassed medium 160 mmHg 6 . In the intact lung HPV is induced when alveolar pO 2 drops below 50 mmHg 25 , a situation which can be obviously mimicked by application of hypoxic-gassed medium.…”

“…Large pre-acinar arteries with inner diameters >40 µm run adjacent to bronchi and bronchioles. Small intra-acinar arteries with inner diameter <40 µm are located at gussets of alveolar septa next to alveolae and alveolar ducts 6 .…”

“…The intra-acinar artery feeding an individual pulmonary acinus with blood represents a partially muscular segment 6 . Likewise, the pulmonary arterial system does not represent a uniform structure regarding the hypoxic response but exhibits marked regional diversity 9,10 .…”

Hypoxic pulmonary vasoconstriction requires connexin 40–mediated endothelial signal conduction

“…This would warrant that HPV responds to local alveolar hypoxia rather than to pulmonary arterial hypoxemia, as has been demonstrated experimentally by a series of seminal studies (3). However, the presence of vascular smooth muscle cells (4,5) and a detectable HPV response (6) is confined to pulmonary arterioles and arteries at least 30 μm in diameter, which are rather remote from the alveolocapillary area of gas exchange. These considerations suggest a spatial dissociation between oxygen sensor and effector in HPV, which would necessitate the existence of a retrograde signaling mechanism from the alveolar gas exchange unit to medium and large PASMC-bearing arterioles and arteries.…”