Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state.
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.
Abraldes
Juan G
JG
Hepatic Hemodynamic Laboratory, Veterans Affairs Connecticut Healthcare System, Digestive Disease 111H, 950 Campbell Ave., New Haven, CT 06516, USA.
Iwakiri
Yasuko
Y
Loureiro-Silva
Mauricio
M
Haq
Omar
O
Sessa
William C
WC
Groszmann
Roberto J
RJ
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism*; D006975:Hypertension, Portal / Q000473:pathology; D007211:Indoles / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000098:blood supply*; D007583:Jejunum / Q000378:metabolism; D008297:Male; D008833:Microcirculation / Q000502:physiology; D009389:Neovascularization, Pathologic; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D017082:Portal Pressure / Q000502:physiology*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D015854:Up-Regulation / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014664:Vasodilation / Q000502:physiology
D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III