Sex shapes capillary flows and oxygen extraction in the middle-aged mouse brain

Abstract

Sex differences in brain aging are well documented, but their origin within the cerebrovascular hierarchy remains unclear. Here we show that cortical blood flow is higher in female than male mice at 15 months of age, at a point when an earlier sex difference in pulsatility and resistance indices has already converged, pial vessel diameter shows no difference between sexes, and estrogen levels are similar between sexes. Using an indicator-dilution and intravascular oxygen measurements using two-photon microscopy, we found that capillary transit-time heterogeneity (CTH) scales more steeply with mean transit time in females, consistent with a passively regulated capillary network, and that this is accompanied by reduced oxygen extraction fraction (OEF) without deficit in arterial oxygen delivery. Spatial transcriptomics reveals that sex differences are organized into distinct regional programs, most prominently in white matter, where a male-associated myelin and axonogenesis signature accompanies reduced white matter volume in females. These molecular and structural differences coincide with elevated hippocampal microglial reactivity and an altered spatial search strategy in females, without any detectable differences in circulating markers of stress, blood-brain barrier integrity, or immunity. Together, these findings indicate that sex differences in the aging brain are expressed at the level of capillary flow regulation and regional tissue programs rather than through bulk cerebral blood flow alone, and that elevated blood flow in females can mask, rather than reflect, adequate tissue oxygenation.

Modeling and validation of parallel co-flows layer widths of viscous liquids in open-capillary trigger valve systems
J. Tokihiro, T. Caira, A. Lin +11
bioRxiv25 Jun 2026PreprintCC BY-NC-NDFull textSystems & synthetic biologybioRxiv
Directional blood flow within a shared capillary network links the nucleus of the solitary tract and area postrema in rats
Kaitlin E. Carson, Ranjan Roy, Javier E. Stern
Communications Biology3 Nov 2026Peer-reviewedCC BY 4.0General biologyNatureCrossref
Integrin α3β1 is required for alveolar-capillary barrier formation through regulation of epithelial differentiation
A. D. Henry, A. L. Alwine, M. J. Niederhuber +22
bioRxiv5 Oct 2026PreprintAll rights reservedFull textDevelopmental biologybioRxiv
Validation of a high throughput fluorescent Capillary Electrophoresis Sodium Dodecyl Sulfate method for monoclonal antibody size heterogeneity assessment
K. D. Luttgeharm, M. Grover, S.-Y. Huang +1
bioRxiv15 Jul 2026PreprintCC BY-NDFull textImmunologybioRxiv
Rapid purity and charge-variant analysis of bispecific antibodies using microfluidic capillary electrophoresis-mass spectrometry
Ruben Cageling, Karin Lubbers-Geuijen, Govert W. Somsen +1
Analytical and Bioanalytical Chemistry22 Aug 2026Peer-reviewedCC BY 4.0Full textImmunologyPMC

Cite

BibTeX RIS

BibTeX

@misc{gutierrezjimenez2026shapes,
  title = {{Sex shapes capillary flows and oxygen extraction in the middle-aged mouse brain}},
  author = {E. Gutierrez-Jimenez and B. Wied and T. B. Lindhardt and S. H. Mikkelsen and R. W. Knopper and C. S. Skoven and O. B. Christensen and V. Dashkovskyi and F. Mrotek and P. M. Rasmussen and M. H. Andresen and A. Krmpot and M. E. Khatib and S. A. Vinogradov and S. Sakadzic and M. F. Jensen and I. Pedroza-Pacheco and D. D. Postnov and L. Lin and J. Just and B. Hansen and L. Ostergaard},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.12.758495},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.12.758495v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Sex shapes capillary flows and oxygen extraction in the middle-aged mouse brain
AU  - E. Gutierrez-Jimenez
AU  - B. Wied
AU  - T. B. Lindhardt
AU  - S. H. Mikkelsen
AU  - R. W. Knopper
AU  - C. S. Skoven
AU  - O. B. Christensen
AU  - V. Dashkovskyi
AU  - F. Mrotek
AU  - P. M. Rasmussen
AU  - M. H. Andresen
AU  - A. Krmpot
AU  - M. E. Khatib
AU  - S. A. Vinogradov
AU  - S. Sakadzic
AU  - M. F. Jensen
AU  - I. Pedroza-Pacheco
AU  - D. D. Postnov
AU  - L. Lin
AU  - J. Just
AU  - B. Hansen
AU  - L. Ostergaard
PY  - 2026
DA  - 2026/10/12
PB  - bioRxiv
DO  - 10.64898/2026.10.12.758495
UR  - https://www.biorxiv.org/content/10.64898/2026.10.12.758495v1
AB  - Sex differences in brain aging are well documented, but their origin within the cerebrovascular hierarchy remains unclear. Here we show that cortical blood flow is higher in female than male mice at 15 months of age, at a point when an earlier sex difference in pulsatility and resistance indices has already converged, pial vessel diameter shows no difference between sexes, and estrogen levels are similar between sexes. Using an indicator-dilution and intravascular oxygen measurements using two-photon microscopy, we found that capillary transit-time heterogeneity (CTH) scales more steeply with mean transit time in females, consistent with a passively regulated capillary network, and that this is accompanied by reduced oxygen extraction fraction (OEF) without deficit in arterial oxygen delivery. Spatial transcriptomics reveals that sex differences are organized into distinct regional programs, most prominently in white matter, where a male-associated myelin and axonogenesis signature accompanies reduced white matter volume in females. These molecular and structural differences coincide with elevated hippocampal microglial reactivity and an altered spatial search strategy in females, without any detectable differences in circulating markers of stress, blood-brain barrier integrity, or immunity. Together, these findings indicate that sex differences in the aging brain are expressed at the level of capillary flow regulation and regional tissue programs rather than through bulk cerebral blood flow alone, and that elevated blood flow in females can mask, rather than reflect, adequate tissue oxygenation.
ER  -

Abstract

Related

Cite