Background. The gas nitric oxide (NO) is an important endothelium-derived relaxing factor, inactivated by rapid combination with heme in hemoglobin. Methods and Results. Awake spontaneously breathing lambs inhaled 5-80 ppm NO with an acutely constricted pulmonary circulation due to either infusion of the stable thromboxane endoperoxide analogue U46619 or breathing a hypoxic gas mixture. Within 3 minutes after adding 40 ppm NO or more to inspired gas, pulmonary hypertension was reversed. Systemic vasodilation did not occur. Pulmonary hypertension resumed within 3-6 minutes of ceasing NO inhalation. During U46619 infusion pulmonary vasodilation was maintained up to 1 hour without tolerance. In the normal lamb, NO inhalation produced no hemodynamic changes. Breathing 80 ppm NO for 3 hours did not increase either methemoglobin or extravascular lung water levels nor modify lung histology compared with control lambs. Conclusions. Low dose inhaled NO (5-80 ppm) is a selective pulmonary vasodilator reversing both hypoxia- and thromboxane-induced pulmonary hypertension in the awake lamb [corrected].

The presence of ''mosaic'' vessels in which both endothelial cells and tumor cells form the luminal surface has profound implications for metastasis, drug delivery, and antivascular therapy. Yet little is known of the frequency, and thus importance, of mosaic vessels in tumors. Using CD31 and CD105 to identify endothelial cells and endogenous green fluorescent protein labeling of tumor cells, we show that Ϸ15% of perfused vessels of a colon carcinoma xenografted at two different sites in mice were mosaic vessels having focal regions where no CD31͞CD105 immunoreactivity was detected and tumor cells appeared to contact the vessel lumen. These regions occupied Ϸ25% of the perimeter of the mosaic vessels, or Ϸ4% of the total vascular surface area in these colon carcinomas. In addition, we found similar numbers of mosaic vessels in human colon carcinoma biopsies. Our results are consistent with the observation that Ϸ10 6 cells are shed daily per g of tumor. More importantly, our data offer a possible explanation for the antivascular effects of cytotoxic agents and suggest potential strategies for targeting the tumor vasculature. Many reports over the past five decades have claimed that cancer cells are located in the walls of tumor blood vessels. This idea was presented as early as 1948 (1), and ultrastructural evidence of tumor-lined vessels was reported in the 1960s by Warren and Shubik (2) and by others in the 1980s (3, 4). This issue also has been addressed in reviews on tumor blood f low (5) and in textbooks of general pathology (6). Sasaki et al. (7) proposed that cancer cells in these vessels might be the sites of adhesion of activated natural killer (A-NK) cells, and more recently, a controversial study by Maniotis et al. (8) concluded that certain uveal melanomas acquire the capability to form blood channels that are not lined by endothelial cells (9 -11).Despite these intriguing observations extending over a halfcentury, very little is known about the presence of tumor cells in vessel walls, and whether some examples are an artifact of the methods used to identify such cells. Other clinically significant questions include: Are blood vessels whose lumen contains tumor cells perfused? Are they unusually leaky? Do the tumor cells actively participate in forming the wall structure? Do they traverse the vessel wall? Do the exposed tumor cells increase the frequency of metastasis? Are they more susceptible to immune attack? Here, we address two of these questions-frequency and perfusion-and examine the significance of mosaic vessels in human colon cancer as well as in corresponding animal models.To approach the problem, we first developed a technique by which cancer cells, endothelial cells, vessel morphology, and blood flow markers could be visualized simultaneously. To uniquely label cancer cells, we transfected the LS174T human colon adenocarcinoma cell line with a constitutively expressing green fluorescent protein (GFP) construct. The resulting fluorescent tumor cells then were implanted into mice and coul...