The team began by mapping what happens to the serine synthesis pathway after cerebral ischemia. Using a mouse model of distal middle cerebral artery occlusion, they found that PHGDH, the rate-limiting enzyme that converts the glycolytic intermediate 3-phosphoglycerate into serine, was markedly elevated in the peri-infarct cortex at 7 and 14 days after stroke. Its downstream partners, PSAT1 and PSPH, rose in parallel, and liquid chromatography-mass spectrometry confirmed a 65 percent increase in serine content in the recovering tissue. The enzyme’s activity, in other words, surges precisely during the delayed window when new vessels begin to form.

Cell-type analysis pinpointed the source. Roughly 77 percent of GFAP-positive astrocytes in the ischemic cortex expressed PHGDH, compared with about 20 percent of CD31-positive endothelial cells, with only scattered signal in neurons, microglia, and oligodendrocytes. Confocal microscopy with three-dimensional reconstruction showed PHGDH-positive astrocytic processes wrapping around and ensheathing peri-infarct blood vessels, placing the enzyme’s product, serine, in direct physical contact with the growing vasculature. Hypoxia experiments in cultured astrocytes and endothelial cells reproduced the effect, suggesting that low oxygen itself triggers the metabolic shift.

To test whether astrocytic PHGDH was truly necessary, the researchers deleted the enzyme selectively in astrocytes by injecting an adeno-associated virus carrying Cre recombinase under the astrocyte-specific GfaABC1D promoter into the cortex of floxed Phgdh mice. The deletion cut PHGDH expression in the ischemic cortex by 66 percent, eliminated most PHGDH-positive astrocytes, and reduced serine concentrations in the injured tissue. The vascular consequences were striking: vascular area and length in the peri-infarct cortex fell by 29 and 22 percent respectively, and the number of proliferating BrdU-positive endothelial cells dropped sharply, along with markers of endothelial tip cells and proangiogenic factors such as VEGFA, VEGFR2, and CD105.

The vessels that did form were also of poorer quality. New vessels after stroke are often leaky, and the tracer experiments made the deterioration vivid. Alexa Fluor 555-cadaverine, a small fluorescent molecule, accumulated far more extensively in the brain parenchyma of PHGDH-deleted mice, and in vivo multiphoton microscopy showed increased leakage of 40-kilodalton FITC-dextran and endogenous IgG from cerebral vessels. Pericyte coverage of capillaries diminished, and the tight junction proteins ZO-1 and claudin-5, which seal the endothelial barrier, were substantially reduced in isolated microvessels. Functional vessel formation, measured by co-labeling BrdU with tomato lectin, fell by 33 percent, and laser speckle imaging confirmed reduced cerebral blood flow. The mice fared worse on behavioral tests of forelimb force and beam walking, linking the vascular failure to lasting neurological deficits.

The flip side proved equally persuasive. When the team overexpressed PHGDH specifically in astrocytes of wild-type mice using a GfaABC1D-driven AAV vector, serine levels in the ischemic cortex rose, endothelial proliferation increased, vascular area and length expanded, and vascular leakage declined. Pericyte coverage improved, perfused capillary length grew, regional cerebral blood flow recovered more fully, and the animals showed significantly better long-term neurological function. Boosting a single metabolic enzyme in support cells, it appeared, could tilt the entire poststroke repair program toward regeneration.

The researchers then traced how astrocyte-derived serine actually reaches the vasculature. Their candidate was SLC38A2, a system A amino acid transporter expressed in brain endothelial cells with a preference for neutral amino acids such as serine. PHGDH overexpression raised SLC38A2 levels in isolated brain microvessels, and when the team silenced the transporter specifically in endothelial cells with a blood-brain barrier-crossing AAV-BR1 shRNA vector, serine content in cortical microvessels fell by 55 percent. Levels of glycine, glutamine, and alanine were unaffected, arguing that the effect was specific to serine transport. Knocking down SLC38A2 also abolished the gains in vascular area, pericyte coverage, and barrier integrity that PHGDH overexpression had produced, identifying the transporter as the essential conduit between astrocytic metabolism and endothelial remodeling.

Downstream of serine delivery, the study implicated the mechanistic target of rapamycin complex 1, or mTORC1, a nutrient-sensing signaling hub long known to drive cell growth and angiogenesis. Astrocytic PHGDH deletion suppressed the phosphorylation of S6 and 4EBP1, canonical mTORC1 readouts, in isolated brain microvessels, while PHGDH overexpression enhanced their activation. Endothelial SLC38A2 silencing likewise inactivated mTORC1 in PHGDH-overexpressing mice. Most tellingly, rapamycin, a pharmacological mTORC1 inhibitor, reduced vascular area and length, worsened tracer leakage and IgG extravasation, and shrank the length of perfused capillaries in stroked animals, phenocopying the loss of PHGDH itself.

The findings reframe astrocytes as metabolic suppliers of poststroke angiogenesis, extending earlier work showing that serine synthesis supports endothelial proliferation and that PHGDH variants in humans disrupt retinal vascular integrity. They also fit a broader picture in which amino acid metabolism, from aspartate to serine, fuels the mTORC1-dependent translation program that growing endothelial cells require. In this scheme, astrocytes act as a metabolic bridge: sensing ischemia, upregulating PHGDH, exporting serine through endothelial SLC38A2, and thereby licensing mTORC1 activation inside the vessel wall.

The authors are careful about the limits of the work. The signals that induce PHGDH after stroke remain unidentified, the contribution of endothelial PHGDH to the same process was not dissected, and serine’s effects on neurons, oligodendrocytes, and other glial lineages await study. Whether other amino acid transporters share the serine delivery role, and whether serine supplementation could help patients, are open questions that will require clinical investigation. Still, the study offers a concrete and druggable axis, PHGDH, SLC38A2, and mTORC1, that connects glial metabolism to vascular repair, and it suggests that boosting this pathway during the subacute phase after ischemic stroke might one day help the brain rebuild its own blood supply.

Subject of Research: The role of astrocytic PHGDH-mediated serine synthesis in poststroke vascular remodeling and recovery after ischemic stroke

Article Title: PHGDH-derived serine is essential for vascular remodeling after stroke

Article References: Liu, Z., Liu, C., Du, P., Geng, X., Wang, S., Wang, Z., Huang, Y., Chang, L., Wang, Y.-C., Fan, W., & Zhao, B.-Q. (2026). PHGDH-derived serine is essential for vascular remodeling after stroke. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2026.09.004

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.09.004

Keywords: ischemic stroke, PHGDH, serine synthesis, astrocytes, angiogenesis, vascular remodeling, SLC38A2, mTORC1, blood-brain barrier, cerebral blood flow, neurovascular unit, stroke recovery