Research

Understanding the Neurovascular Unit and Blood-Brain Barrier in Brain Health and Cancer

The brain is supported by an intricate network of blood vessels that does far more than deliver oxygen and nutrients. Brain blood vessels interact continuously with neurons, astrocytes, pericytes, immune cells and the surrounding extracellular matrix (ECM) to form specialized multicellular structures known as neurovascular units (NVUs). These interactions establish and maintain the blood-brain barrier (BBB), regulate vascular growth and remodeling and allow the brain to adapt to changes in its local environment.

The McCarty Laboratory studies how communication between neural and vascular cells maintains the organization and function of the NVU and how these interactions are altered in disease, with a particular focus on brain cancer and glioblastoma (GBM). We are interested in the molecular mechanisms that allow cells within the NVU to sense and respond to their extracellular environment, with an emphasis on cell adhesion, ECM signaling and communication between glial cells, tumor cells and the cerebral vasculature.

Our work combines genetically engineered mouse models, primary cell culture systems, human brain tumor specimens and molecular and spatial profiling approaches. By integrating these complementary systems, we seek to understand how cellular interactions and signaling networks establish distinct vascular and BBB states in the normal brain and how these states are remodeled during tumor progression.

Examining the Neurovascular Unit and Regulation of the Blood-Brain Barrier

The BBB is a defining feature of the cerebral vasculature and is essential for maintaining the specialized environment required for normal brain function. BBB properties are not determined solely by endothelial cells. Instead, they emerge from interactions among endothelial cells, pericytes, astrocytes, other glial cells and the vascular basement membrane and surrounding ECM.

The McCarty Laboratory has a longstanding interest in understanding how glial cells communicate with cerebral endothelial cells to regulate vascular development and BBB function. Our studies have demonstrated that adhesion and signaling pathways operating at the interface between perivascular neural cells and endothelial cells are essential for normal brain vascular development. In particular, the ECM receptor αVβ8 integrin expressed by perivascular neural cells can activate latent transforming growth factor-β (TGFβ) complexes within the ECM, providing a mechanism through which glial cells regulate signaling in neighboring endothelial cells.

These studies established an important principle underlying our current research: the ECM is not simply a structural scaffold surrounding blood vessels, but an active signaling compartment that controls communication between cells within the NVU. We continue to investigate how adhesion receptors, ECM proteins and growth factor signaling pathways cooperate to regulate vascular morphogenesis, endothelial differentiation and BBB integrity. We are also interested in the specialized functions of perivascular astrocytes and other glial populations that closely associate with cerebral blood vessels. Using genetically engineered mouse models and molecular profiling approaches, we are identifying the signals produced by these cells that regulate endothelial behavior and BBB function. These studies provide a framework for understanding how normal glial–vascular communication is altered during brain injury and cancer.

Defining BBB and Neurovascular States in Glioblastoma

GBM profoundly alters the normal organization of the NVU. Tumor-associated blood vessels can become highly abnormal, while changes in endothelial, astrocytic, pericyte, immune and ECM compartments contribute to BBB dysfunction. At the same time, the BBB within a tumor is not uniformly disrupted. Different regions of a GBM can display markedly different vascular and barrier properties.

We are therefore developing approaches to define distinct NVU and BBB states within brain tumors and to determine how these states influence tumor behavior and therapeutic response. Using human tumor specimens, spatial transcriptomics, molecular profiling and experimental mouse models, we are mapping the cellular programs that characterize different vascular microenvironments within glioma.

A central question is how interactions between tumor cells and the NVU produce these distinct states. We are examining how glioma-derived signals alter endothelial cells and how changes in endothelial and ECM states, in turn, influence tumor cell invasion and growth. We are also investigating how therapeutic interventions alter the tumor-associated vasculature and BBB. This work has important implications for understanding why therapies that target tumor cells or blood vessels can produce different effects in different regions of the same tumor. By defining the molecular and cellular states of the NVU, we hope to identify microenvironmental vulnerabilities that can be therapeutically targeted.

Studying ECM Adhesion and Signaling Pathways in Glioma Progression

The ability of glioma cells to invade surrounding brain tissue is a defining feature of GBM and a major barrier to effective treatment. We study the intracellular pathways through which ECM adhesion receptors regulate this invasive behavior.

Our research has identified signaling and cytoskeletal pathways associated with the cytoplasmic domain of β8 integrin and other adhesion receptors. These studies have revealed previously unrecognized interactions between integrins, protein tyrosine phosphatases, cytoskeletal regulators and protein turnover pathways that control tumor cell behavior.

More broadly, we are interested in how integrin signaling intersects with growth factor, TGFβ, focal adhesion and cytoskeletal pathways to regulate glioma cell invasion and adaptation to the tumor microenvironment. Rather than examining these pathways in isolation, our current work seeks to understand how they function as interconnected signaling networks that allow tumor cells to respond dynamically to the ECM and surrounding vascular environment.

These studies are performed using primary patient-derived glioma cells, genetically engineered models and in vivo models of tumor growth and invasion. The goal is to identify signaling mechanisms that can be targeted to disrupt the interactions that allow glioma cells to survive, invade and adapt within the brain.

Understanding and Targeting the Brain Tumor Microenvironment

The long-term goal of the McCarty Laboratory is to understand how cell–cell and cell–ECM interactions within the NVU shape brain tumor biology. We view the glioma microenvironment as an integrated system in which tumor cells, blood vessels, glial cells, immune cells and the ECM continuously exchange signals.

Our current research brings together several complementary areas of investigation:

• Neurovascular unit and BBB biology: defining the cellular and molecular mechanisms that establish vascular and barrier states in the brain
• ECM and adhesion biology: identifying ECM components and adhesion receptors that regulate communication between cells in the brain microenvironment
• Glioma–vascular interactions: determining how tumor cells remodel the NVU and exploit vascular and ECM signaling pathways to promote growth and invasion
• Spatial organization of the tumor microenvironment: using spatial and molecular profiling to define distinct tumor, vascular and stromal states within human gliomas
• Therapeutic response and BBB remodeling: understanding how tumor therapies alter vascular and BBB states and identifying mechanisms that may be exploited to improve treatment