Endothelial cell toll-like receptor 4 regulates fibrosis-associated angiogenesis in the liver

Abstract

Angiogenesis defines the growth of new blood vessels from preexisting vascular endothelial networks and corresponds to the wound healing process that is typified by the process of liver fibrosis. Liver fibrosis is also associated with increased endotoxin within the gut lumen and its associated portal circulation. However, the interrelationship of gut endotoxin and its receptor, toll‐like receptor 4 (TLR4), with liver fibrosis and associated angiogenesis remains incompletely defined. Here, using complementary genetic, molecular, and pharmacological approaches, we provide evidence that the pattern recognition receptor that recognizes endotoxin, TLR4, which is expressed on liver endothelial cells (LECs), regulates angiogenic responses both in vitro and in vivo. Mechanistic studies have revealed a key role for a cognate TLR4 effector protein, myeloid differentiation protein 88 (MyD88), in this process, which culminates in extracellular protease production that regulates the invasive capacity of LECs, a key step in angiogenesis. Furthermore, TLR4‐dependent angiogenesis in vivo corresponds to fibrosis in complementary liver models of fibrosis. Conclusion: These studies provide evidence that the TLR4 pathway in LECs regulates angiogenesis through its MyD88 effector protein by regulating extracellular protease production and that this process is linked to the development of liver fibrosis. (HEPATOLOGY 2010;)

Aquaporin-1 Promotes Angiogenesis, Fibrosis, and Portal Hypertension Through Mechanisms Dependent on Osmotically Sensitive MicroRNAs

“…Indeed, most strategies targeting angiogenic molecules have shown benefit in preclinical animal models of liver disease. 11,[31][32][33][34] In this context, our study extends the current knowledge of an emerging anti-angiogenic target, AQP1, by providing direct in vivo evidence that AQP1 regulates the angiogenesis, fibrosis, and portal hypertension that occurs after BDL; and defining a novel, molecular, fine-tuning mechanism involving osmotically sensitive miRs that may contribute to the pathological overexpression of AQP1 during cirrhosis. We previously demonstrated that AQP1 is overexpressed in the angiogenic neovasculature within fibrotic septa in human cirrhosis and in CCl 4 -induced liver injury in C57 black mice.…”

Hepatic sinusoids in liver injury, inflammation, and fibrosis: new pathophysiological insights

“…Bacterially derived lipopolysaccharides (LPS) bind to their receptor TLR-4 expressed on SEC, inducing injury and inflammation [11]. Interestingly, recent studies have shown that LPS can also induce fibrosis-associated angiogenesis by interacting with TLR-4, highlighting the role of SEC in the so-called gut-liver axis [12,13].…”

Toll-Like Receptors in Angiogenesis

“…Jagavelu and colleagues recently demonstrated a key role for the TLR4/MyD88 axis during VEGF production and the subsequent angiogenic process in liver endothelial cells following LPS stimulation [41]. Likewise, mycoplasma infections could be accompanied by enhanced angiogenesis and microvascular remodeling, which are features of chronic inflammation as elicited by Mycoplasma pulmonis infections of the respiratory tract [42].…”