Portal branch ligation induces a hepatic arterial buffer response, microvascular remodeling, normoxygenation, and cell proliferation in portal blood-deprived liver tissue

Abstract

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 ∼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.

Portal Cavernoma Cholangiopathy: Consensus Statement of a Working Party of the Indian National Association for Study of the Liver

“…37,38 Subsequently, rapid development of venous collaterals and formation of varices as well as cavernoma occur. These dilated venous collaterals exert external pressure and protrude into the thin and pliable CBD and the hepatic ducts ( Figure 1).…”

Induction of Tumor Growth After Preoperative Portal Vein Embolization: Is It a Real Problem?

“…37 However, most malignant tumors tolerate hypoxia quite well. 38 In addition, hypoxia may induce cellular changes that can result in more aggressive phenotypes with increased potential for local invasive growth, distant tumor spreading, and resistance to therapy.…”

“…40 In the late phase after ligation, tissue remodeling takes place which is dominated by cell proliferation. 37 Hence, tumor proliferation may be promoted in this late phase after PVE.…”

“…42 Clinical and experimental studies demonstrate a significant increase in hepatic arterial blood flow in the occluded liver lobes resulting from an increase in common hepatic arterial flow. 37,43 After portal vein occlusion, sinusoidal perfusion is derived almost totally from arterial blood supply. 44 Because liver tumors are mainly fed by the hepatic artery, the hepatic arterial buffer response potentially stimulates tumor growth in the embolized liver lobes.…”

Hepatic Arterial Infusion with Tumor Necrosis Factor-α Induces Early Hepatic Hyperperfusion

“…For monitoring of hepatic microvascular blood flow, laser Doppler fluxmetry (LDF; PeriFlux System 5000, Perimed, Stockholm, Sweden) was used [30,31]. Blood flow was measured by placing the laser Doppler probe on three different areas of the liver surface in the center of the right and the left lobe.…”