Lin Kooi Ong, PhD

Chan SJ, Esposito E, Hayakawa K, Mandaville E, Smith RAA, Guo S, Niu W, Wong PT-H, Cool SM, Lo EH, Nurcombe V. Vascular Endothelial Growth Factor 165-Binding Heparan Sulfate Promotes Functional Recovery From Cerebral Ischemia. Stroke. 2020;51:2844–2853.

Angiogenesis and neurogenesis are crucial processes for brain recovery after stroke. While the brain has the capacity to form new cerebral blood vessels and to generate new neurons from neural stem cells after stroke, these self-repair mechanisms are limited. Therefore, strategies to promote brain restorative processes beyond the endogenous recovery are highly desirable. In this study, Chan and colleagues demonstrated that an exogenously applied heparan sulfate with increased affinity for vascular endothelial growth factor was able to enhance angiogenesis and neurogenesis within the peri-infarct regions, as well as to promote neurological recovery after experimental stroke.

The team first purified heparan sulfate variant 7, a glycosaminoglycan sugar which has increased affinity for vascular endothelial growth factor, and tagged the molecule with fluorescent dye. The team experimentally induced stroke in rats using transient middle cerebral artery occlusion, and then they delivered heparan sulfate (or placebo) into the right lateral ventricle of the brain at day 4 after experimental stroke. The rats were assessed for neurological deficits, and rats treated with heparan sulfate showed a modest improvement in the modified neurological score 7 days after treatment (heparan sulfate vs placebo; 7.3±0.4 vs 8.8±0.5). Furthermore, the team tracked the distribution of the fluorescent tagged heparan sulfate and found the signals co-localized with endothelial cells (Collagen IV) and in neural stem cells (Nestin) within the peri-infarct regions. Histology analysis showed that heparan sulfate treatment enhances angiogenesis and neurogenesis (by approximately 3 to 7 folds) within the peri-infarct regions, without compromising the blood brain barrier integrity. The team also performed a series of cell culture studies and demonstrated that the heparan sulfate most likely stimulates vascular endothelial growth factor signaling.

While the findings from this study are promising, there are several points that require consideration. To improve translational value of this novel treatment, future preclinical studies should use both males and females, older animals, and animals with different comorbidities (hypertension, diabetes). Further, the clinically relevant route of heparan sulfate administration, such as intravenous injection, should be investigated.