Visual experience-driven switch in endothelial metabolic transporters is essential for cerebrovascular maturation

N. Kim; E.-Y. Choi; S. Chae; J.-Y. Jeong; H. K. Kim; W.-J. Oh

doi:10.64898/2026.10.26.762059

AI summary · DOI: 10.64898/2026.10.26.762059 · bioRxiv: Neuroscience

Visual experience-driven switch in endothelial metabolic transporters is essential for cerebrovascular maturation

N. Kim, E.-Y. Choi, S. Chae, J.-Y. Jeong, H. K. Kim, W.-J. Oh

Original paper Published on 28 Oct. 2026 bioRxiv preprint License: CC BY-NC-ND 4.0 Also in: fr

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The essentials

In developing mice, visual experience promotes an endothelial MCT1-to-GLUT1 transporter switch required for vascular and blood–brain barrier maturation, involving endothelial TGF-β signaling and astrocytic MCT1.

Question

How does sensory-driven neuronal activity coordinate the transition from cerebrovascular growth to blood–brain barrier maturation? The study asks whether regulated endothelial metabolic transporter expression mediates this transition.

Method

The authors profiled endothelial ribosome-associated RNA from mouse visual cortex at postnatal days 10 and 30, with four mice per group, and compared developmental changes with a published light-stimulation single-cell RNA sequencing dataset. They combined dark rearing, neuronal inhibition, cell-type-specific conditional deletions, and endothelial AAV-mediated MCT1 overexpression with vascular imaging, tracer permeability assays, and biochemical measurements. Experiments in human hCMEC/D3 endothelial cells tested TGF-β pathway inhibitors and lactate effects on transporter expression, migration, and tube formation.

Findings

Result Dark rearing and pharmacological neuronal inhibition attenuated the developmental decrease in endothelial MCT1 and increase in GLUT1.
See the passage in the paper
Both visual deprivation and pharmacological suppression of neuronal activity both attenuated the developmental decline in endothelial MCT1 and the reciprocal increase in GLUT1, suggesting that physiological sensory experience helps determine the timing of this metabolic transition.
Result Sustained endothelial MCT1 expression reduced vascular growth measures, decreased ZO-1 and Claudin-5, and increased permeability to small tracers without detectable IgG or Evans Blue leakage.
See the passage in the paper
In this developmental window, sustained endothelial MCT1 expression increased permeability to low-molecular-weight tracers and reduced the tight junction proteins ZO-1 and Claudin-5, whereas no detectable leakage of endogenous IgG or Evans Blue was observed.
Result Early endothelial deletion of either Mct1 or Tgfbr2 impaired vascular growth, indicating that these components are needed before their later developmental attenuation.
See the passage in the paper
Endothelial-specific deletion of Mct1 significantly reduced vessel diameter, vascular density, and vessel length compared with control littermates (Figures 5B‒E). Similarly, endothelial-specific deletion of Tgfbr2 resulted in significant reductions in all three vascular parameters (Figures 5F‒I).
Authors’ interpretation The authors interpret their perturbation experiments as supporting an endothelial TGF-β1–MCT1–lactate positive-feedback loop that sustains the early transporter state.
See the passage in the paper
The underlying mechanism involves an endothelial TGF-β1‒MCT1‒lactate positive-feedback loop that sustains the early MCT1-high state, while its developmental attenuation facilitates the transition to an MCT1-low/GLUT1-high state.
Result Astrocytic Mct1 haploinsufficiency maintained endothelial MCT1 and TGF-β1 expression, reduced GLUT1 induction, and impaired vascular and barrier maturation.
See the passage in the paper
Consistent with this model, astrocytic Mct1 haploinsufficiency sustained endothelial MCT1 and TGF-β1 expression, suppressed GLUT1 induction, and impaired vascular and BBB maturation, alongside increased active TGF-β1 levels and gelatinase activity.

Limitations

The mechanism through which lactate reinforces endothelial TGF-β signaling, including any contribution from extracellular acidification, remains unresolved.
See the passage in the paper
The precise mechanism by which lactate reinforces endothelial TGF-β signaling remains unresolved.
The molecular pathway connecting visual experience-driven neuronal activity to astrocytic MCT1 upregulation remains unknown.
See the passage in the paper
However, the mechanisms by which visual experience-driven neuronal activity upregulates astrocytic MCT1 remain unclear.
Astrocytic loss-of-function analyses used heterozygous animals because most homozygous knockout mice did not survive beyond postnatal day 14.
See the passage in the paper
Because most homozygous knockout mice failed to survive beyond P14, subsequent analyses were performed using heterozygous conditional knockout littermates, which exhibited normal growth during this period.

Why it matters

The authors argue that endothelial transporter switching is an actively regulated developmental program rather than merely an adaptation to substrate availability. Their proposed neuron–astrocyte–endothelial mechanism links sensory experience and intercellular metabolic signaling to the timing of vascular growth and barrier maturation.

Written by AI from the paper. Passages are checked word for word against the text we analysed; the rest may contain errors.

AI-generated keywords: Blood–brain barrier; Sensory experience; MCT1–GLUT1 switch; TGF-β1 signaling; Astrocytes

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Comprehensive Summary
Layman's Summary
Blog article
Original abstract

This bioRxiv preprint examines how sensory experience helps developing brain blood vessels transition from active growth to a mature blood–brain barrier (BBB). It focuses on a developmental switch in endothelial nutrient transporters: MCT1, which transports lactate and other monocarboxylates, declines, while GLUT1, which transports glucose, increases. The authors investigate whether neuronal activity regulates this switch and whether the switch actively contributes to vascular maturation rather than merely reflecting changing brain energy requirements. The study combines mouse genetics, visual deprivation, viral gene delivery, endothelial gene-expression profiling, and experiments using the human brain endothelial cell line hCMEC/D3. Using endothelial RiboTag profiling, the researchers compared the visual cortex at postnatal day 10 (P10), before eye opening, with P30, after visual experience begins, using four mice per group. They identified 1,462 differentially translated genes: 670 increased and 792 decreased at P30. Comparison with a published light-stimulation single-cell dataset revealed 95 overlapping activity-responsive genes. Among the differentially translated transporters, only MCT1 and GLUT1 showed significant, concordant changes in both datasets, with MCT1 decreasing and GLUT1 increasing. Protein measurements confirmed that the endothelial transporter switch occurred around eye opening, at approximately P14. Dark rearing for one month attenuated both MCT1 downregulation and GLUT1 upregulation. Suppressing neuronal activity with daily muscimol injections at 0.5 mg/kg from P10 to P14 produced a similar partial effect. To test the functional importance of MCT1 downregulation, the authors delivered an endothelial-targeting virus at P3 and examined the mice at P14. Sustained MCT1 expression reduced vascular density, diameter, and length; suppressed GLUT1; and decreased the tight-junction proteins ZO-1 and Claudin-5. It also increased leakage of approximately 1-kDa cadaverine and 3-kDa dextran, without detectable leakage of endogenous immunoglobulin G or Evans blue. These findings indicate a selective barrier defect rather than unrestricted permeability. Mechanistic experiments implicated endothelial TGF-β1 signaling in maintaining the early MCT1-high, GLUT1-low state. Pharmacological inhibition of TGF-β signaling lowered MCT1 and increased GLUT1 in cultured cells. Endothelial deletion of Tgfbr2 or Tgfb1, induced at P3 and assessed at P7, supported this relationship in mice. Endothelial cells appeared to be the principal functional source of the relevant TGF-β1. MCT1 overexpression increased brain lactate, endothelial TGF-β1, downstream SMAD2 phosphorylation, vascular gelatinase activity, and active TGF-β1, while reducing collagen IV. Conversely, endothelial Mct1 deletion reduced lactate and TGF-β1. In culture, 10 mM lactate increased TGF-β1 and promoted migration and tube formation; an MCT1 inhibitor attenuated these angiogenic responses. Importantly, early deletion of either Mct1 or Tgfbr2 impaired vascular growth, suggesting that this pathway supports early development but becomes detrimental when sustained too long. Astrocytes emerged as potential regulators of this transition. Astrocytic MCT1 expression increased between P7 and P14, whereas dark rearing suppressed this increase. Astrocyte-specific loss of one Mct1 copy prolonged endothelial MCT1 and TGF-β1 expression, reduced GLUT1 and vascular density, and increased small-tracer leakage. Most homozygous astrocytic knockout mice did not survive beyond P14, necessitating analyses of heterozygous mice. The authors conclude that visual experience coordinates a neuron–astrocyte–endothelial program that shifts vessels from lactate-associated growth toward BBB maturation. However, astrocytic clearance of perivascular lactate, local acidification, and their causal connections to TGF-β1 activation remain proposed mechanisms rather than directly established steps. Many experiments involved only three to seven animals or biological samples per group, precise effect sizes were not consistently reported, and the findings’ relevance beyond the developing mouse visual cortex remains uncertain. The study has not yet been peer reviewed.

How Visual Experience May Help the Brain’s Blood Vessels Grow Up

Opening the eyes marks more than a new way to explore the world. In developing mice, visual experience may also help brain blood vessels shift from active growth toward a mature, protective blood–brain barrier. A new bioRxiv preprint suggests that this transition involves changing which nutrients the cells lining those vessels are equipped to transport.

The paper, “Visual experience-driven switch in endothelial metabolic transporters is essential for cerebrovascular maturation,” is by N. Kim, E.-Y. Choi, S. Chae, J.-Y. Jeong, H. K. Kim, and W.-J. Oh. It investigates whether a switch between two transporters helps drive vascular maturation, rather than simply reflecting the developing brain’s changing energy needs. The findings have not yet been peer reviewed.

From Lactate Transport to Glucose Transport

The blood–brain barrier relies on specialized endothelial cells that line brain blood vessels. These cells restrict the movement of many substances while allowing essential nutrients to enter. Two transporters are central to this study: MCT1, which carries lactate and other monocarboxylates, and GLUT1, which transports glucose.

The researchers compared endothelial gene translation in the mouse visual cortex at postnatal day 10, before eye opening, and day 30, after visual experience begins. Using endothelial RiboTag profiling with four mice per group, they identified 1,462 differentially translated genes: 670 increased and 792 decreased at the later age.

Comparison with a published light-stimulation dataset identified 95 overlapping activity-responsive genes. Among the differentially translated transporters, only MCT1 and GLUT1 showed significant, matching changes across both datasets: MCT1 declined while GLUT1 increased. Protein measurements placed this switch around eye opening, approximately postnatal day 14.

What Happens Without Visual Input?

To test whether sensory experience mattered, the team raised mice in darkness for one month. Dark rearing weakened both sides of the normal transition: MCT1 did not decline as much, and GLUT1 did not increase as much.

Suppressing neuronal activity with daily muscimol injections from postnatal days 10 to 14 produced a similar partial effect. Together, these experiments support a role for neuronal activity in regulating the transporter switch. Because neither intervention completely prevented it, other developmental signals likely contribute too.

Keeping the Growth Program Running Has Costs

The key functional question was whether persistent MCT1 expression would interfere with maturation. The researchers delivered an endothelial-targeting virus at postnatal day 3 to sustain MCT1 expression, then examined the mice at day 14.

The resulting vessels had reduced density, diameter, and length. They also showed lower GLUT1 expression and reduced levels of ZO-1 and Claudin-5, proteins that help form tight junctions between endothelial cells.

Barrier testing revealed an important distinction. Small tracers—approximately 1-kDa cadaverine and 3-kDa dextran—leaked more readily, but the researchers detected no leakage of endogenous immunoglobulin G or Evans blue. This points to a selective barrier defect, not an unrestricted opening of the blood–brain barrier.

A Pathway That Helps Early but Hurts When Prolonged

Mechanistic experiments implicated TGF-β1 signaling in maintaining the early MCT1-high, GLUT1-low state. Blocking TGF-β signaling in cultured human brain endothelial cells lowered MCT1 and increased GLUT1. Endothelial deletion of either Tgfbr2, a receptor gene, or Tgfb1 in mice supported this relationship. Endothelial cells appeared to be the main functional source of the relevant TGF-β1.

Sustained MCT1 expression increased brain lactate, endothelial TGF-β1, and downstream SMAD2 phosphorylation. It also increased vascular gelatinase activity and active TGF-β1 while reducing collagen IV, a component of the vessels’ supporting matrix. Conversely, endothelial Mct1 deletion reduced lactate and TGF-β1.

In culture, lactate promoted endothelial migration and tube formation, and an MCT1 inhibitor attenuated these responses. Yet deleting Mct1 or Tgfbr2 early also impaired vascular growth. The implication is about timing: this pathway supports early development, but prolonged activity can disrupt the later transition toward mature vessels.

Astrocytes May Help Coordinate the Handoff

Astrocytes, support cells that interact closely with vessels, emerged as potential regulators. Their MCT1 expression increased between postnatal days 7 and 14, and dark rearing suppressed that increase.

Removing one astrocytic Mct1 copy prolonged endothelial MCT1 and TGF-β1 expression, reduced GLUT1 and vascular density, and increased small-tracer leakage. Most mice lacking both astrocytic copies did not survive beyond day 14, so the researchers analyzed heterozygous mice.

The proposed explanation is that astrocytes help clear lactate near vessels, allowing endothelial cells to leave their growth-associated state. However, that clearance mechanism—and the proposed connections involving local acidification and TGF-β1 activation—was not directly established.

A Promising Model, With Limits

The study links sensory experience, nutrient transport, and vascular development in a compelling model. However, many experiments used only three to seven animals or biological samples per group, precise effect sizes were not consistently reported, and relevance beyond the developing mouse visual cortex remains uncertain. For now, the findings suggest that transporter changes may help actively coordinate vascular maturation—not merely accompany it.

Created on 02 Nov. 2026

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Weekly letter Presented in "Brain and behaviour this week" of 2 November 2026. Brain and behaviour this week: What wiring explains—and what context changes

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Visual experience-driven switch in endothelial metabolic transporters is essential for cerebrovascular maturation

The essentials

Question

Method

Findings

Limitations

Why it matters

Read further

Definitions

How Visual Experience May Help the Brain’s Blood Vessels Grow Up

From Lactate Transport to Glucose Transport

What Happens Without Visual Input?

Keeping the Growth Program Running Has Costs

A Pathway That Helps Early but Hurts When Prolonged

Astrocytes May Help Coordinate the Handoff

A Promising Model, With Limits

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