Surreal illustration of liver-shaped blood vessels representing angiogenesis in NASH treatment

Unlocking NASH Treatment: Can Angiogenesis Hold the Key to a Cure?

Rhea Morgan in Health & Wellness December 2025 • 4 min read.

"A deeper look into how targeting blood vessel growth could revolutionize the fight against fatty liver disease and its progression to cancer."

The role of angiogenesis in the progression of liver diseases, specifically nonalcoholic steatohepatitis (NASH), is gaining significant attention. Angiogenesis, the process of forming new blood vessels, is intricately linked to fibrogenesis, where proangiogenic mediators drive injury and promote the development of fibrosis.

Understanding these mechanisms is crucial, as NASH, a severe form of nonalcoholic fatty liver disease (NAFLD), can advance to hepatocellular cancer (HCC). Given the global impact of these diseases, exploring new therapeutic avenues is paramount.

Recent studies have highlighted the potential of targeting angiogenesis to treat NASH and prevent its progression. This article delves into these advancements, focusing on the innovative work exploring the angiopoietin-Tie2 signaling pathway and its implications for NASH treatment.

Targeting Angiogenesis: A New Approach to NASH Treatment

Surreal illustration of liver-shaped blood vessels representing angiogenesis in NASH treatment

Research has demonstrated that increased angiogenesis, indicated by elevated levels of CD34 immunostaining, is evident in liver samples from NASH patients, particularly those with advanced fibrosis. This observation has led to investigations into angiogenic signaling pathways in preclinical NASH models.

One key pathway involves vascular endothelial growth factor (VEGF) and placental growth factor (PIGF). Studies in mice fed a methionine-choline deficient (MCD) diet—a model for NASH—showed increased angiogenesis alongside elevated angiogenic and inflammatory mediators. Blocking VEGF Receptor-2 reduced the angiogenic response and improved inflammation and steatosis. Targeting VEGF signaling may provide a therapeutic avenue for managing hepatic steatosis and inflammation associated with abnormal angiogenic responses.

Angiogenesis plays a significant role in the progression of NASH and liver fibrosis.
Targeting VEGF signaling can reduce the angiogenic response and improve liver health in preclinical models.

The angiopoietin-Tie2 receptor complex plays a critical role in angiogenesis. Tie receptors, including Tie1 and Tie2, interact with angiopoietins (ANG1 and ANG2) to regulate angiogenesis. ANG1 promotes vascular homeostasis, while ANG2 can act as either an agonist or antagonist of Tie2 signaling, depending on the context. In inflammatory conditions, Tie1 cleavage leads to ANG2 dominance, promoting abnormal vasculature prone to leakage.

Future Directions: Paving the Way for Clinical Trials

Studies reveal elevated ANG2 levels in NASH patients, correlating with inflammation and neovascularization markers. Inhibiting ANG2 signaling via Tie2, using an engineered antibody (L1-10), has shown promising results in preclinical models. Administering L1-10 reduced inflammation and fibrosis in MCD-fed mice, and decreased abnormal angiogenesis.

Further studies demonstrated that L1-10 treatment could mitigate the development of HCC in a streptozotocin-western diet model of NASH. While steatosis and inflammation remained largely unaffected, the treatment reduced tumor burden and decreased the expression of tumor-associated markers.

These studies highlight the potential of targeting ANG2-Tie interactions in NASH treatment. Further research is needed to explore the underlying mechanisms and determine the long-term effects of these interventions. Ultimately, these findings could pave the way for clinical trials and novel therapeutic strategies for NASH and associated complications.

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Everything You Need To Know

How is angiogenesis related to the development of nonalcoholic steatohepatitis (NASH)?

Angiogenesis, the formation of new blood vessels, is intricately linked to fibrogenesis in nonalcoholic steatohepatitis (NASH). Proangiogenic mediators drive injury and promote the development of fibrosis, which can lead to hepatocellular cancer (HCC). Understanding these mechanisms is crucial for exploring new therapeutic avenues to combat NASH and prevent its progression.

What role does vascular endothelial growth factor (VEGF) play in nonalcoholic steatohepatitis (NASH), and how can it be targeted for treatment?

Research indicates that increased angiogenesis, evidenced by elevated levels of CD34 immunostaining, is found in liver samples from nonalcoholic steatohepatitis (NASH) patients, particularly those with advanced fibrosis. This has spurred investigations into angiogenic signaling pathways. One key pathway involves vascular endothelial growth factor (VEGF) and placental growth factor (PIGF). Studies blocking VEGF Receptor-2 reduced the angiogenic response and improved inflammation and steatosis, suggesting that targeting VEGF signaling may help manage hepatic steatosis and inflammation associated with abnormal angiogenic responses.

What is the significance of the angiopoietin-Tie2 receptor complex in the context of nonalcoholic steatohepatitis (NASH) and angiogenesis?

The angiopoietin-Tie2 receptor complex is a critical regulator. Tie receptors, including Tie1 and Tie2, interact with angiopoietins (ANG1 and ANG2) to regulate angiogenesis. ANG1 promotes vascular homeostasis, while ANG2 can act as either an agonist or antagonist of Tie2 signaling, depending on the context. In inflammatory conditions, Tie1 cleavage leads to ANG2 dominance, promoting abnormal vasculature prone to leakage. Understanding how to balance ANG1 and ANG2 is key to therapeutic intervention.

What do current studies indicate about the potential of inhibiting ANG2 signaling in treating nonalcoholic steatohepatitis (NASH)?

Studies have revealed elevated ANG2 levels in nonalcoholic steatohepatitis (NASH) patients, correlating with inflammation and neovascularization markers. Inhibiting ANG2 signaling via Tie2, using an engineered antibody (L1-10), has shown promising results in preclinical models. Administering L1-10 reduced inflammation and fibrosis in methionine-choline deficient (MCD)-fed mice and decreased abnormal angiogenesis. This suggests that targeting ANG2 signaling could be a viable therapeutic strategy.

How could targeting angiogenesis in nonalcoholic steatohepatitis (NASH) help prevent the progression to hepatocellular cancer (HCC)?

Targeting angiogenesis, specifically through pathways like vascular endothelial growth factor (VEGF) and the angiopoietin-Tie2 receptor complex, could potentially prevent the progression of nonalcoholic steatohepatitis (NASH) to more severe conditions like hepatocellular cancer (HCC). By inhibiting factors such as ANG2 with agents like the L1-10 antibody, researchers aim to reduce inflammation, fibrosis, and abnormal blood vessel formation in the liver, ultimately slowing or halting disease progression. This approach focuses on addressing the underlying mechanisms that drive NASH, offering a more targeted and potentially effective treatment strategy.