Brain Vasculature Studies Using Advanced Optical Imaging

Technology Overview

Dr. Andy Shih

In the human brain, an estimated 400 miles of blood vessels deliver blood to more than 85 billion neurons. Neuroscientist Andy Shih, PhD, uses advanced optical imaging to study neurovascular development, structure and function – from individual molecules to multicellular systems. His lab images the dynamics of blood and cells in the brains of living, unanesthetized mouse models.

Dr. Shih is an expert in multiphoton microscopy, a high-resolution imaging method that produces real-time 3D images of the internal components of the brain, its cells and cellular components. The Shih Lab uses multiphoton microscopy to create brain angiograms, which are detailed images of the brain’s vasculature, using fluorophores and fluorescent reporters.

The images capture entire vascular networks at the resolution of individual capillaries, enabling detailed assessment of blood flow and blood-brain barrier (BBB) function. With multiphoton microscopy, the Shih Lab can simultaneously measure vascular functions, quantify cells that make up the vascular wall (e.g., endothelial cells, mural cells, astrocytes), and monitor neural cell activity using the fluorescent calcium indicator GCaMP.

Multiphoton microscopy can be used in any mouse model. The Shih Lab has experience imaging commercially available mice and custom mouse models of injury such as stroke, hypoperfusion and traumatic brain injury, and chronic diseases such as cerebral small vessel disease associated with aging and Alzheimer’s disease.

The researchers developed their own chemogenetically engineered mouse model that allows them to directly modify mural cells to control blood flow during studies of vasodilation and vasoconstriction. This mouse model supports studies examining if therapeutics can improve blood flow by dilating cerebral vessels.

The Shih Lab can measure changes in:

• Physiological parameters such as blood pressure, tissue oxygenation and BBB function.
• Movement of fluorescently tagged compounds across the BBB under normal or compromised BBB conditions.
• Blood flow in all vessels with characterization of blood cells, including immunotherapy cells, and their movement through vessels.
• Pharmacokinetic (PK) metrics including drug half-life, breakdown products, cell uptake, duration in the brain and response to medications administered by different routes immediately after introduction or at steady state.
• Morphology, size and activity of neurons and other brain cells, including endothelial cells, astrocytes and pericytes, and their response to therapeutics.
• Activation and signaling of brain cells.
• White matter that is often disrupted in disease and injury.

The Shih Lab also has expertise in mass spectrometry, histology and confocal microscopy. They have capabilities in light-sheet microscopy, which creates 3D images of fixed tissues that have been cleared of lipids and other obscuring compounds, to study animal and human postmortem brain samples.

The Shih Lab aims to be an in vivo test bed for evaluating therapeutics meant to increase angiogenesis or blood flow in the brain. Dr. Shih is also interested in industry partnerships to use advanced brain imaging to study neurovascular development and repair. This work is relevant to multiple conditions including autism, sickle cell disease and brain injury from hypoxia during human development.  

Stage of Development

• Preclinical in vivo
• Advanced in vivo imaging
• Fixed tissue imaging and analysis

Partnering Opportunities

• Sponsored research agreement
• Collaborative research opportunity
• Consultation agreement
• Licensing agreement
• Contracted service or research agreement

Learn More

• Andy Shih, PhD
• Shih Lab

Publications

Stamenkovic S, Schmid F, Gurler G … Shih AY. Impaired capillary-venous drainage contributes to gliosis and demyelination in mouse white matter during aging. Nat Neurosci. 2025;28(9):1868-1882.

Bonney SK, Nielson CD, Sosa MJ … Shih AY. Capillary regression leads to sustained local hypoperfusion by inducing constriction of upstream transitional vessels. Proc Natl Acad Sci USA. 2024;121(37):e2321021121.

Berthiaume AA, Schmid F, Stamenkovic S … Shih AY. Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure. Nat Commun. 2022;13(1):5912.

Coelho-Santos V, Berthiaume AA, Ornelas S … Shih AY. Imaging the construction of capillary networks in the neonatal mouse brain. Proc Natl Acad Sci USA. 2021;118(26):e2100866118.

Hartmann DA, Berthiaume AA, Grant RI … Shih AY. Brain capillary pericytes exert a substantial but slow influence on blood flow. Nat Neurosci. 2021;24(5):633-645.

Last updated March 2026