PHGDH-derived serine is essential for vascular remodeling after stroke

Astrocytic-vascular crosstalk contributes to vascular repair and remodeling after brain injury. 3‑Phosphoglycerate dehydrogenase (PHGDH), the rate-limiting serine synthetic enzyme, has emerged as a crucial factor in cell growth and metabolism. However, the role of PHGDH in ischemic stroke is poorly understood.

This study aimed to determine whether PHGDH-derived serine contributes to neovascularization and functional recovery after ischemic stroke.

We employed astrocyte-specific PHGDH deletion and PHGDH overexpressing mice to evaluate the role of PHGDH in poststroke neovascularization, vascular remodeling and functional recovery. To explore the interaction between vascular solute carrier family 38 member 2 (SLC38A2) and astrocytic PHGDH, we knocked down SLC38A2 in PHGDH-overexpressing mice using an AAV-BR1 carrying shRNA (shSlc38a2) virus. Moreover, we treated mice with mammalian target of rapamycin complex1 (mTORC1) inhibitor rapamycin to assess the effect of mTORC1 on angiogenesis and vascular integrity after ischemic stroke.

The expression of PHGDH was significantly upregulated in astrocytes during stroke recovery, which led to the accumulation of serine in the ischemic cortex. Deletion of PHGDH in astrocytes decreased the amount of serine and enhanced vascular permeability, impaired neovascularization and the formation of functional vessels, and decreased vascular perfusion and cerebral blood flow at 14 days after ischemic stroke. In contrast, overexpression of astrocytic PHGDH increased serine levels, promoted neovascularization and vascular remodeling, and improved blood flow and long-term functional recovery. These effects were mediated through the SLC38A2 transporter, and endothelial silencing of SLC38A2 resulted in decreased vascular serine levels and the inactivation of mTORC1, and blocked neovascularization and vascular repair in PHGDH-overexpressing mice. Moreover, infusion of rapamycin impaired vascular repair and plasticity.

Our observations demonstrate that poststroke neovascularization is regulated by astrocytic-vascular interaction involving PHGDH-mediated elevation of serine.