While portal hypertension accounts for significant mortality in patients with liver cirrhosis, its molecular pathogenesis remains undefined. The Overall Objective of this grant is to define how intravascular pressures increase in the hepatic sinusoid, which is the initiating step of portal hypertension. Liver injury leads to tissue edema and early matrix deposition which increases stiffness in the interstitial Space of Disse. How mechanical forces such as stiffness regulates endothelial cell signaling and gene transcription to influence portal pressure is a gap in knowledge. Recent studies reveal unanticipated importance of glycolytic metabolism in diverse and critical endothelial cell functions. In this regard, our Preliminary Data in liver endothelial cells (LEC) shows that interstitial stiffness: 1) triggers glycolysis dependent remodeling of focal adhesions and actin stress fibers which culminates in, 2) histone acetylation dependent production and release of the CXCL1 neutrophil chemokine, and that 3) neutrophils can form neutrophil extracellular traps (NETS) and microthrombi in the hepatic sinusoids. NETS are extruded nuclear proteins from neutrophils implicated in thrombosis. Indeed, clinical evidence from patients with portal hypertension demonstrates microthrombi in the hepatic sinusoids although their pathogenic role in portal hypertension has not been previously defined. We have utilized these novel findings to generate the Central Hypothesis of the current proposal; that glycolysis dependent mechanotransduction in LEC leads to CXCL1 release that mediates neutrophil derived sinusoidal microthrombi to increase portal pressure.
The Aims are to test the sub-hypotheses that: 1) Glycolysis is required for mechanotransduction in LEC.
Aim 1 a will examine mechanisms how interstitial stiffness increases glycolytic activity by recruiting glycolytic enzymes to focal adhesions for their activation.
Aim 1 b will test how glycolysis induces actin polymerization to promote mechanotransduction from focal adhesions to the nucleus by increasing nuclear pore size and enabling nuclear translocation of the mechanosensitive transcription activator YAP. 2) LEC mechanotransduction leads to CXCL1 release that recruits neutrophils to LEC.
Aim 2 a will explore how YAP recruits the histone acetyltransferase, p300, from the CXCL1 enhancer to the CXCL1 promoter to deposit histone marks that activate gene transcription.
Aim 2 b will examine functional effects of released CXCL1 on neutrophil adhesion to LEC. 3) CXCL1 recruited neutrophils produce NETS leading to sinusoidal microthrombi and portal hypertension.
Aim 3 will use a combination of genetic and pharmacologic interventions to disrupt glycolytic enzyme function and YAP-p300 activation of CXCL1 production and release, to ascertain effects on portal hypertension development in mice in vivo.
The Aim will also utilize innovative imaging techniques including atomic force microscopy, magnetic resonance elastography, and intravital microscopy to measure cellular and organ changes in stiffness in coordination with NETS, microthrombi, and portal hypertension. Thus, this proposal will explore how mechanotransduction drives metabolism to regulate chromatin and gene transcription in the hepatic sinusoids. This novel and innovative line of inquiry will define an LEC dependent model of portal hypertension and set a trajectory towards new and significant advances to treat portal hypertension in humans.

Public Health Relevance

Portal hypertension is the major cause of morbidity and mortality in patients with cirrhosis. This work is focused on developing new molecular targets for portal hypertension and also testing these therapies preclinically. Thus, it has the potential to lead to treatments for humans suffering from this syndrome.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Sherker, Averell H
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Mayo Clinic, Rochester
United States
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