Angiogenesis and Progression of ACLD

Angiogenesis, the formation of new blood vessels from preexisting vasculature, is a necessary mechanism during liver regeneration to perfuse tissues deprived of oxygen and nutrients. This process is observed in liver disease, with cirrhotic livers being more vascularized than healthy livers. In the setting of chronic liver injury, the regenerative process of angiogenesis can divert into a pathogenic process. Unveiling the mechanisms of angiogenesis in liver health and disease may elucidate the determining factors of hepatic regenerative and degenerative responses. Positioned at the intersection of these two response pathways are sinusoidal endothelial cells (SECs), the constituents comprising the fenestrated barrier in sinusoids. SECs are the gatekeepers to the sinusoid microenvironment due to their selective physical barrier and the angiocrine signals they secrete to promote liver homeostasis. These angiocrine signals exhibit an interdependent relationship with the pathways that regulate angiogenesis. A symbiotic relationship between angiocrine signaling and angiogenesis is necessary to facilitate appropriate regenerative responses. In the setting of persistent and chronic liver injury, SECs change to a capillarized phenotype, concomitantly inducing a change in the respective angiocrine pathways. Consequently, the regulatory capacity of SECs is compromised, opening the gates to multiple pathophysiological mechanisms. The symbiotic relationship between angiocrine signaling and angiogenesis is perturbed, allowing for an unregulated angiogenic response—pathological angiogenesis. Pathological angiogenesis compromises intrahepatic pressure regulation and affords the stimulation of pro-fibrogenic pathways. This, in turn, invokes hypoxic and inflammatory pathways. These pathophysiological mechanisms reciprocally influence one another, culminating in a decompensating cascade that erodes liver health, drives disease progression, and gives rise to advanced chronic liver disease (ACLD). Eventually, these diseased livers succumb to the effects of this decompensating cascade. This engenders increases in portal pressure, subsequently giving rise to decompensated events like ascites, variceal hemorrhage, and hepatic encephalopathy.