Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 310, Issue 11, Pages H1735-H1747Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00109.2016
Keywords
postcapillary venule in rat mesentery; curved and straight portions; flow-induced nitric oxide production; microvessel permeability to albumin; N-G-monomethyl-L-arginine
Funding
- National Institutes of Health (National Cancer Institute) grant [SC1CA153325-01]
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Nitric oxide (NO) at different concentrations may promote or inhibit tumor growth and metastasis under various conditions. To test the hypothesis that tumor cells prefer to adhere to the locations with a higher endothelial NO production in intact microvessels under physiological flows and to further test that inhibiting NO production decreases tumor cell adhesion, we used intravital fluorescence microscopy to measure NO production and tumor cell adhesion in postcapillary venules of rat mesentery under normal and reduced flow conditions, and in the presence of an endothelial nitric oxide synthase (eNOS) inhibitor, N-G-monomethyl-L-arginine (L-NMMA). Rats (SD, 250-300 g) were anesthetized. A midline incision (similar to 2 inch) was made in the abdominal wall, and the mesentery was taken out from the abdominal cavity and spread over a coverslip for the measurement. An individual postcapillary venule (35-50 mu m) was first loaded with 4,5diaminofluorescein diacetate (DAF-2 DA), a fluorescent indictor for NO. Then the DAF-2 intensity was measured for 30 min under a normal or reduced flow velocity, with and without perfusion with MDA-MB-231 breast cancer cells, and in the presence of L-NMMA. We found that tumor cells prefer to adhere to the microvessel locations with a higher NO production such as curved portions. Inhibition of eNOS by L-NMMA attenuated the flow-induced NO production and reduced tumor cell adhesion. We also found that L-NMMA treatment for similar to 40 min reduced microvessel permeability to albumin. Our results suggest that inhibition of eNOS is a good approach to preventing tumor cell adhesion to intact microvessels under physiological flows.
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