increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state. Am J Physiol Gastrointest Liver Physiol 290: G980 -G987, 2006; doi:10.1152/ajpgi.00336.2005.-Increased nitric oxide (NO) is the main factor leading to the hyperdynamic circulation associated with advanced portal hypertension (PHT), but the initial mechanisms and the magnitude of increase in portal pressure required to trigger NO production are not known. We addressed these issues by studying systemic and splanchnic hemodynamics and endothelial NO synthase (eNOS) and VEGF expression in rats with different degrees of portal hypertension. Portal vein ligation (PVL) performed over needles of three different calibers (16-, 18-, and 20-gauge) yielded different degrees of PHT and portosystemic shunting. Compared with sham rats, all three groups of PVL rats exhibited features of hyperdynamic circulation. Rats with minimal portal hypertension (PVL with a 16-gauge needle) showed an early increase in VEGF and eNOS expression selectively at the jejunum. Immunofluorescence showed that VEGF expression was located in highly vascularized areas of the mucosa. Inhibition of VEGF signaling markedly attenuated the increase in eNOS expression. In conclusion, mild increases in portal pressure are enough to upregulate eNOS at the intestinal microcirculation, and this occurs, at least in part, through VEGF upregulation. cirrhosis; vasodilation A HALLMARK of portal hypertension (PHT) syndrome is a hyperdynamic circulatory state, characterized by splanchnic and peripheral vasodilation, increased plasma volume, and increased cardiac output (CO) (18). This hyperkinetic syndrome is the result of an increased production of vasodilators, mainly nitric oxide (NO), in the peripheral and splanchnic circulation (for a review, see Ref. 42). A number of mechanisms, including shear stress (20), bacterial translocation (39, 40), or portosystemic shunting (PSS) (1, 2), have been proposed to explain the upregulation of endothelial NO synthase (eNOS), the isoform that accounts for the increased NO production in PHT. However, it has been demonstrated that eNOS activation occurs before any of these mechanisms is present (22,43), and the signals that initially trigger NO hyperproduction in PHT are still poorly understood.The partial portal vein ligation (PVL) model has been shown to reproduce the systemic and hemodynamic abnormalities in PHT (37). Furthermore, its highly predictable chronobiology has allowed the elucidation of the sequences of events leading to hyperdynamic circulation (8,33). Thus this model also offers the opportunity to sequentially evaluate the molecular mechanisms leading to the hemodynamic abnormalities observed in hyperdynamic circulation. In that regard, a recent study from our laboratory suggested that, in the commonly used PVL model, in which portal vein stenosis is calibrated over a 20-gauge needle (37), the myogenic response that occurs in the s...

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Increased levels of intestinal VEGF are thought to worsen portal hypertension. The cause of the increase in the level of intestinal VEGF found during cirrhosis is not known. The aim of this study is to demonstrate a relationship between portal pressure (PP) and intestinal/ plasma VEGF levels in different stages of fibrosis/cirrhosis. In this experiment, rats were exposed to carbon tetrachloride (CCl4) for 6, 8 and 12 weeks. At the end of exposure, the three groups of rats exhibited three different stages of pathology: non-cirrhotic, early fibrotic and cirrhotic, respectively. For those rats and their age-matched controls, PP and intestinal/plasma VEGF levels were measured. Rats inhaling CCl4 for 12 weeks developed portal hypertension (18.02 ± 1.07 mmHg), while those exposed for 6 weeks (7.26 ± 0.58 mmHg) and for 8 weeks (8.55 ± 0.53 mmHg) did not. The rats exposed for 12 weeks also showed a 40% increase in the level of intestinal VEGF compared to the controls (P < 0.05), while those rats exposed to CCl4 inhalation for 6 and 8 weeks did not. There was a significant positive correlation between PP and intestinal VEGF levels (r2 = 0.4, P < 0.005). Plasma VEGF levels were significantly elevated in those rats exposed to 12 weeks of CCl4 inhalation (63.7 pg/ml, P < 0.01), compared to the controls (8.5 pg/ml). However, no correlation was observed between PP and plasma VEGF levels. It is concluded that portal pressure modulates intestinal VEGF levels during the development of cirrhosis.

Purpose. We examined current osteoporosis prevention practices in patients with inflammatory bowel disease (IBD) on chronic steroid using the 2003 American Gastroenterological Association guidelines as standard of care. Methods. We identified all IBD patients followed at the Oklahoma City VA Medical Center from January 2003 to December 2010, who had been on daily oral steroids (prednisone ≥5 mg or budesonide ≥6 mg) for ≥3 consecutive months. Associations of calcium and vitamin D (vitD) prescribing and bone mineral density (BMD) testing with patient characteristics were examined by logistic regression. Results. Sixty-three of 384 consecutive patients met inclusion criteria. Among 86 steroid courses, calcium and vitD were concurrently prescribed in 46%, and BMD was tested in 30%. There was no association of demographic and clinical characteristics with calcium/vitD prescribing and BMD testing. By multivariate analysis, steroid initiation after 2006, compared to before 2006, was associated with a significant increase in calcium (OR = 3.17 and P = 0.02) and vitD (OR = 2.96 and P = 0.02) prescribing and BMD testing (OR = 4.63 and P = 0.004). Conclusions. We observed a low, yet increasing, adherence to osteoporosis prevention guidelines in IBD since 2003, which highlights the need for continued physician education to enhance guideline awareness and implementation.