Portal branch ligation induces a hepatic arterial buffer response, microvascular remodeling, normoxygenation, and cell proliferation in portal blood-deprived liver tissue.
Portal branch ligation (PBL) may prevent liver failure after extended hepatic resection. However, clinical studies indicate that tumors within the ligated lobe develop accelerated growth. Although it is well known that tumor growth depends on the host's microvascularization, there is no information about how PBL affects the hepatic microcirculation. Our aims were to determine hepatic artery response, liver microcirculation, tissue oxygenation, and cell proliferation after PBL. Therefore, we used intravital multifluorescence microscopy, laser-Doppler flowmetry, immunohistochemistry, and biochemical techniques to examine microcirculatory responses, microvascular remodeling, and cellular consequences after left lateral PBL in BALB/c mice. During the first 7 days, PBL induced a reduction of left hilar blood flow by approximately 50%. This resulted in 80% sinusoidal perfusion failure, significant parenchymal hypoxia, and liver atrophy. After 14 days, however, left hilar blood flow was found to be restored. However, remodeling of the microvasculature included a rarefaction of the sinusoidal network, however, without substantial perfusion failure, compensated by a hepatic arterial buffer response and significant sinusoidal dilatation. This resulted in normalization of tissue oxygenation, indicating arterialization of the ligated lobe. Interestingly, late microvascular remodeling was associated with increased endothelial nitric oxide synthase expression, significant hepatocellular proliferation, and weight gain of the ligated lobe. Thus PBL induces only an initial microcirculatory failure with liver atrophy, followed by a hepatic arterial buffer response, microvascular remodeling, normoxygenation, and hepatocellular proliferation. This may explain the accelerated tumor progression occasionally observed in patients after PBL.
Kollmar
Otto
O
Dept. of General, Visceral, Vascular, and Pediatric Surgery, Univ. of Saarland, D-66421 Homburg/Saar, Germany. otto.kollmar@uniklinikum-saarland.de
Corsten
Marcus
M
Scheuer
Claudia
C
Vollmar
Brigitte
B
Schilling
Martin K
MK
Menger
Michael D
MD
D000818:Animals; D017209:Apoptosis; D001284:Atrophy; D015687:Cell Hypoxia; D049109:Cell Proliferation; D004790:Enzyme Induction; D005260:Female; D006499:Hepatic Artery / Q000503:physiopathology*; D007150:Immunohistochemistry; D017078:Laser-Doppler Flowmetry; D008026:Ligation; D008099:Liver / Q000098:blood supply* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008102:Liver Circulation; D051379:Mice; D008807:Mice, Inbred BALB C; D008833:Microcirculation / Q000503:physiopathology; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D008930:Mitochondria, Liver / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D009929:Organ Size; D010101:Oxygen Consumption; D011169:Portal Vein / Q000601:surgery*; D013997:Time Factors
D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat