Pathological Role of Hepatocyte Growth Factor in Ischemic Stroke

Hepatocyte growth factor (HGF) was formerly a hepatocyte mitogen, but it's now an angiogenic and endothelium-specific growth factor, which regulates cellular and tissue mitosis, morphology, angiogenesis and apoptosis. HGF and its receptor, c-Met, both are expressed in plaques of atherosclerosis, where they might play a role in atherosclerosis and cerebrovascular disorders such as ischemic stroke. High levels of HGF in these plaques can result in neovascularisation and leukocyte infiltration and inflammation. These processes can further trigger angiogenesis in the plaques, causing them to become more unstable and prone to rupture, and eventually cause acute ischemic stroke.

It is possible that the serum HGF can be a valuable biomarker to detect carotid atherosclerosis and for risk of thromboembolic stroke later on. But we don't know whether elevated HGF is a risk factor for ischemic stroke itself, or an outcome of stroke, or just another risk factor for cardiovascular disease.

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• Pathogenic Mechanism Analysis Services for Stroke
• Neuroprotective Agent Development for Stroke

Hepatocyte Growth Factor as a Promising Therapeutic Agent for Stroke

Meanwhile, HGF has long been known to be neuroprotective and angiogenic after a cerebrovascular event. HGF in the mid-acute stroke state was strongly associated with clinical recovery in the post-acute stroke state: sustained long-term neuroprotection resulting from the end of treatment, which leads to greater motor-coordination recovery, indicates that HGF is responsive in brain tissue and facilitates cerebral remodeling, and these are the attributes that make it an ideal stroke drug.

Mechanisms of HGF-Induced Long-Term Neuroprotection and Stroke Recovery

By being neuroprotective and angiogenic, HGF could be used to boost functional recovery in ischemic stroke. Hence a good therapeutic plan for ischemia would be not only to induce collateral blood vessel formation (therapeutic angiogenesis) but also to delay the death of neurons. HGF helps promote angiogenesis in the ischemic penumbra, increases microcirculation, and seals the blood-brain barrier, reducing cerebral edema. Further, HGF acts as neuroprotective by preventing the death of neurons and blocking gliosis via the sphingosine-1-phosphate pathway that limits the number and migration of astrocytes involved in glial scarring.

HGF functions by binding to the c-Met receptor and activating several downstream signaling pathways (PI3K/Akt, MAPK, STAT) which control angiogenesis, glial scar formation, neurogenesis, and anti-apoptotic activity that then saves the brain from ischemic insult.

The salves of HGF reach beyond the spine and peripheral nerves. In spinal cord research, intrathecal injections of recombinant HGF preserved corticospinal fibers and myelin sheaths, enhanced functional recovery, and maintained spinal cord integrity (MRI). HGF also promotes grafted neural stem cells in injured spinal tissue to survive, differentiate, and form synapses. HGF can be successfully restored through gene therapy in peripheral nerve injury, which has further demonstrated its promise as a therapy in many neurodegenerative diseases.

Fig.1. HGF promotes neural differentiation. (Doeppner, et al., 2011)

Conclusion

HGF shows a significant correlation with the severity of carotid atherosclerosis, which can increase the risk of thromboembolic stroke. Conversely, higher HGF levels are associated with improved functional outcomes after stroke. To better understand the role of elevated HGF in the development of cerebral infarction, as well as its diagnostic and prognostic capabilities, further studies involving larger patient populations are needed. Additionally, exploring the therapeutic potential of HGF in enhancing recovery following acute stroke is warranted.

1. Doeppner, T. R., et al. (2011). Acute hepatocyte growth factor treatment induces long-term neuroprotection and stroke recovery via mechanisms involving neural precursor cell proliferation and differentiation. Journal of Cerebral Blood Flow & Metabolism, 31(5), 1251-1262.