Francesca Tinelli, MS
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.
Vascular endothelial growth factor-165 (VEGF165) is a member of the VEGF family that potently sustains angiogenesis and neurogenesis by stimulating proliferation and migration of endothelial and neural progenitor cells (NPC). Both processes are critical for the post-stroke recovery because they should restore the correct blood flow and supply oxygen and nutrients, enhancing brain functionality. Conversely, VEGF165 also regulates vascular permeability and increases blood-brain barrier (BBB) permeability, thus amplifying brain edema and neuroinflammation. Because of its powerful therapeutic potential, VEGF165 has been proposed as a treatment for improving stroke recovery.
Heparan sulfate (HS) proteoglycans are glycoproteins involved in several processes, such as cell adhesion and motility, signaling, transport, endocytosis, lysosomal degradation, cytoskeletal organization and basement membrane organization. They play an important role in angiogenesis, regulating VEGF receptor (VEGF-R) activation rates. The HS7 variant, thanks to the high affinity for VEGF165, stabilizes it in the extracellular matrix and thus safely enhances the effects of locally produced VEGF after stroke.
The article by Chan et al. evaluated the potential in vitro angiogenic and neurogenic effects of HS7 in rat brain endothelial cell line 4 (RBE4) and NPC. Male Sprague-Dawley rats were also subjected to 100 minutes of transient focal cerebral ischemia and treated, after 4 days, with either Phosphate Buffered Saline (PBS) or HS7. Infarct volume, behavioral sequelae, markers of angiogenesis and neural stem cell proliferation were assessed one week later. The authors concluded that VEGF-HS7 binding: (i) significantly enhances the proliferation of both RBE4 and NPC, through the VEGF-R2 pathway; (ii) increases the capability of tube formation of RBE4 cells; and (iii) promotes the differentiation of NPC toward neurons. In the rat model, they demonstrated that the HS7, injected in the peri-infarct region close to VEGF-A, improves neurological outcome, preserving infarct size and vascular permeability, without blood brain barrier damage. Moreover, HS7 variant improves angiogenesis and neurogenesis in vivo, as demonstrated by the increase in collagen IV/Ki67 and nestin/Ki67.
In conclusion, HS7 promotes angiogenesis and neurogenesis induced by local endogenous VEGF165, preventing neuroinflammation and blood brain barrier alterations found also in comorbidities of stroke (i.e., hypertension, diabetes mellitus and hyperlipidemia). For these reasons, although further studies are necessary to validate these phenomenological findings, HS7 could represent a valid therapeutic option for enhancing recovery after a stroke.