Effects of pathological flow on pulmonary artery endothelial production of vasoactive mediators and growth factors.
BACKGROUND
Alterations in pulmonary blood flow are often associated with the initiation and progression of pulmonary vascular disease. However, the cellular mechanisms involved in mediating flow effects in the pulmonary circulation remain unclear. Depending on the disease condition, flow may be extremely low or high. We therefore examined effects of pathologically low and high flow on endothelial production of factors capable of affecting pulmonary vascular tone and structure as well as on potential underlying mechanisms.


METHODS
Flow effects on pulmonary endothelial release of NO, PGF(1a), ET-1 and TxB(2), on expression of total and phosphorylated eNOS as well as Akt, and on VEGF were examined. Additionally, in a coculture system, effects of flow-exposed endothelial cells on smooth muscle (SM) proliferation and contractile protein were studied.


RESULTS
Compared to physiological flow, pathologically high and low flow attenuated endothelial release of NO and PGF(1a), and enhanced release of ET-1. Physiological flow activated the Akt/eNOS pathway, while pathological flow depressed it. Pathologically high flow altered VE-cadherin expression. Pathologically high flow on the endothelium upregulated alpha-SM-actin and SM-MHC without affecting SM proliferation.


CONCLUSIONS
Physiological flow leads to production of mediators which favor vasodilation. Pathological flow alters the balance of mediator production which favors vasoconstriction.
Li
Min
M
Department of Pediatrics and CVP Research, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262, USA.
Stenmark
Kurt R
KR
Shandas
Robin
R
Tan
Wei
W
D000199:Actins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002417:Cattle; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D016228:Endothelial Growth Factors / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D040542:Mechanotransduction, Cellular; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D011460:Prostaglandins F / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D011673:Pulsatile Flow; D013314:Stress, Mechanical; D013929:Thromboxane B2 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000378:metabolism*; D014665:Vasodilator Agents / Q000378:metabolism*; D000099152:Cadherin 5
D000199:Actins; D015703:Antigens, CD; D015820:Cadherins; D016228:Endothelial Growth Factors; D019332:Endothelin-1; D018995:Myosin Heavy Chains; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D011460:Prostaglandins F; D051057:Proto-Oncogene Proteins c-akt; D013929:Thromboxane B2; D042461:Vascular Endothelial Growth Factor A; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000099152:Cadherin 5; C100006:prostaglandin F1