Pericyte and Endothelial Cell Responses within Murine Cerebral Capillaries After Blood Flow Cessation

Abstract

ABSTRACT The microcirculation, encompassing terminal arterioles, capillaries, and venules, plays a pivotal role in the distribution of blood throughout tissues, with capillaries acting as the primary sites for oxygen and nutrient delivery as well as waste product removal. A critical component of the microcirculation is the vascular pericyte (PC), which is essential for angiogenesis and the regulation of microvascular biomechanics. This thesis focuses on the cerebrovascular network, particularly the cerebral microcirculation, and investigates the role of pericytes in maintaining blood-brain barrier (BBB) integrity and neurovascular homeostasis. In this work We highlighted the dynamic interactions between pericytes, endothelial cells, and the extracellular matrix (ECM) in the regulation of microvascular stability and BBB function. underscoring the importance of pericytes in normal physiology and disease. The work investigated the effects of biophysical cues from blood flow on cerebral microcirculation, utilizing an ex vivo murine brain slice model to investigate pericyte behavior under altered hemodynamic conditions. Findings from these experiments suggest that pericytes play an active role in capillary wall remodeling and that changes in hemodynamic forces may lead to vascular dysfunction. Additionally, we optimized a protocol for isolating and characterizing BBB capillaries, along with an analysis of the results that delivers a more precise representation of cerebrovascular structures and their responses across various research contexts. This refined methodology lays the groundwork for future studies on BBB dysfunction in neurological diseases like Alzheimer's and stroke. The thesis also includes an in-depth examination of pericyte morphology and its heterogeneity, and their interactions with the ECM, We believe these approaches offer highly valuable, complementary techniques for characterizing pericytes and gaining insight into their role in the development, maturation, and dysfunction of the microvasculature. The insights gained from this work contribute to a more comprehensive understanding of the molecular and biomechanical mechanisms governing cerebrovascular function. As such, this thesis lays the groundwork for future studies aimed at developing therapeutic interventions targeting pericyte function and BBB integrity, with implications for treating a variety of neurological disorders.