Dr. Hu’s research has contributed to a broader understanding of how vascular cells regulate tissue homeostasis, regeneration, and disease. During his postdoctoral research, he identified endothelial cell-derived angiopoietin-2 (Ang2) as a spatiotemporal regulator of liver regeneration, coordinating the proliferation of hepatocytes and liver sinusoidal endothelial cells to restore liver mass. This work advanced the understanding of the vasculature as not only a conduit for blood flow but also an active regulator of organ regeneration and repair (Hu et al., Science, 2014).

After establishing his independent laboratory, Dr. Hu has focused on the mechanisms and functional significance of endothelial–pericyte crosstalk, as well as its potential for therapeutic intervention. His laboratory established a systematic landscape of endothelial–pericyte communication and identified NO–sGC signaling as a key pathway mediating their interaction during angiogenesis and vascular homeostasis. They demonstrated that NO–sGC signaling is essential for maintaining vascular integrity in adult tissues: disruption of endothelial–pericyte communication causes pericyte detachment and vascular leakage during lung injury, whereas activation of this pathway preserves pericyte coverage, maintains vascular integrity, and ameliorates tissue injury (He et al., J Exp Med, 2023). The laboratory further showed that NO–sGC signaling is dispensable for pericyte recruitment but essential for pericyte ensheathment and vessel maturation during tumor angiogenesis. Disruption of this pathway reduces pericyte coverage of tumor vessels, thereby sensitizing tumors to anti-angiogenic therapy and enhancing its therapeutic efficacy (Zhu et al., EMBO J, 2024).

Extending this work to organ fibrosis, his laboratory has used single-cell transcriptomics and genetic approaches to define the dynamic changes and transitions between functional states of hepatic stellate cells (HSCs), the specialized pericytes of the liver, during fibrosis. These studies revealed a cellular roadmap of HSC activation and demonstrated that HSCs are the major source of fibrogenic myofibroblasts in hepatotoxin-induced liver fibrosis. The laboratory further found that NO–sGC signaling is required for HSC quiescence but is absent from portal fibroblasts, and that this signaling is specifically disrupted during HSC-driven liver fibrosis. Pharmacological activation of the pathway suppresses HSC activation and reduces fibrosis, identifying NO–sGC signaling as a potential therapeutic target for HSC-associated liver fibrosis (Yang et al., Hepatology, 2021).

His laboratory has also investigated how endothelial cell fitness determine vascular regeneration and remodeling. By combining complementary genetic, lineage-tracing, transplantation, and parabiosis approaches, they demonstrated that endothelial cell fitness is a key determinant of vascular regeneration, resolving longstanding controversy over the contribution of bone marrow-derived cells and showing that an intact liver vasculature regenerates predominantly through expansion of resident endothelial cells (Singhal et al., J Exp Med, 2018). In another study, the laboratory identified endothelial KANK4 as a regulator of arteriogenesis and demonstrated that KANK4 controls vessel lumen size by potentiating VEGFR2 signaling in a TALIN-1-dependent manner, revealing a previously unrecognized mechanism by which endothelial cells intrinsically regulate VEGFR2 signaling and vascular remodeling (Zhang et al., ATVB, 2022).