VASCULAR BIOLOGY
Brain angiogenesis, blood-brain barrier and stroke
The blood vessels of the brain are absolutely critical; for example, interruption of brain blood flow can result in devastating stroke. We study Gpr124, a G protein-coupled receptor expressed on brain vasculature. We showed that gene knockout of Gpr124 results in a near-total loss of angiogenic invasion into the embryonic brain, resulting in forebrains that are essentially avascular. The few blood vessels that successfully enter the brain in Gpr124 ko mice aggregate abnormally into glomeruloid aggregates that are hemorrhagic and result in embryonic lethality (Kuhnert et al., Science, 2010).
Gpr124 is also required to stabilize brain blood vessels during pathologic angiogenesis such as in brain tumors and stroke. Upon adult Gpr124 genetic deletion, experimental brain tumors and stroke become extremely hemorrhagic because of leaky blood vessels (Chang et al., Nature Medicine 2017).
Mice with knockout of Gpr124, a distinct membrane receptor RECK, or Wnt7a/7b all share an extremely similar CNS angiogenesis phenotype. Biochemically, we have demonstrated that Gpr124 actually co-purifies with RECK and that RECK helps to stabilize newly produced Wnt7 (Vallon et al., Cell Reports 2018). Also, Gpr124 appears to rely on its extracellular, not intracellular, domain to signal (Yuki et al., Development 2024).
From the above results, we are further exploring the Gpr124/RECK/Wnt7 pathway and methods for its pharmacologic regulation as relevant to stroke and brain tumor treatment, such as through bioengineered Frizzled-4-selective WNT surrogates (Nature Communications 2023).
