Stretch activates nitric oxide production in pulmonary vascular endothelial cells in situ.
Whereas endothelial responses to shear stress have been studied extensively, the responses to circumferential vascular stretch are yet poorly defined. Circumferential stretch in pulmonary microvessels is largely determined by the transmural pressure gradient, hence by both vascular perfusion and alveolar ventilation pressures. Here, we have studied the production of nitric oxide (NO) by the endothelial nitric oxide synthase (eNOS) in two different models of vascular stretch in the intact lung: In isolated-perfused rat lungs, vascular stretch was induced by elevation of vascular pressure. In situ digital fluorescence microscopy revealed stretch-dependent NO production, which was localized to capillary endothelial cells and inhibited by NOS blockers. In isolated-perfused mouse lungs, vascular stretch was generated by ventilation with elevated negative pressure. Stretch-induced phosphorylation of Akt and eNOS in lung endothelial cells was demonstrated by immunohistochemistry and increased NO production by in situ fluorescence microscopy. Stretch-induced endothelial responses in both models were abrogated by pretreatment with phosphatidylinositol-3-OH kinase inhibitors. These findings demonstrate that circumferential stretch activates NO production in pulmonary endothelial cells by a signaling cascade involving phosphatidylinositol-3-OH kinase, Akt, and eNOS and that this response is independent from the mechanical factors causing vascular distension.
Kuebler
Wolfgang M
WM
Division of Pulmonary Pharmacology, Research Center Borstel, Borstel, Germany.
Uhlig
Ulrike
U
Goldmann
Torsten
T
Schael
Gregor
G
Kerem
Alexander
A
Exner
Kay
K
Martin
Christian
C
Vollmer
Ekkehard
E
Uhlig
Stefan
S
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology*; D066298:In Vitro Techniques; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011311:Pressoreceptors / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D011652:Pulmonary Circulation / Q000502:physiology; D011661:Pulmonary Stretch Receptors / Q000502:physiology*; D051381:Rats; D033081:Shear Strength; D015398:Signal Transduction / Q000502:physiology
D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat; C494920:Akt1 protein, rat