Microvascular networks are vital components of the cardiovascular system, performing many key roles in maintaining the health and homeostasis of the tissues and organs in which they develop. As discussed in this review, the molecular and cellular components within the microcirculation orchestrate critical processes to establish functional capillary beds, including organization of endothelial cell (EC) polarity, guiding investment of vascular pericytes (PCs), and building the specialized extracellular matrix (ECM) that comprises the vascular basement membrane (vBM). Herein, we further discuss the unique features of the microvasculature in the central nervous system (CNS), focusing on the cells contributing to the neurovascular unit (NVU) that form and maintain the blood‐brain barrier (BBB). With a focus on vascular PCs, we offer basic and clinical perspectives on neurovascular‐related pathologies that involve defects within the cerebral microvasculature. Specifically, we present microvascular anomalies associated with glioblastoma multiforme (GBM) including defects in vascular‐immune cell interactions and associated clinical therapies targeting microvessels (ie, vascular‐disrupting/anti‐angiogenic agents and focused ultrasound). We also discuss the involvement of the microcirculation in stroke responses and potential therapeutic approaches. Our goal was to compare the cellular and molecular changes that occur in the microvasculature and NVU, and to provide a commentary on factors driving disease progression in GBM and stroke. We conclude with a forward‐looking perspective on the importance of microcirculation research in developing clinical treatments for these devastating conditions.
- Award ID(s):
- 1752339
- NSF-PAR ID:
- 10431511
- Date Published:
- Journal Name:
- Frontiers in Physiology
- Volume:
- 13
- ISSN:
- 1664-042X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
more » « less
Abstract -
more » « less
Abstract Vascular pericytes provide critical contributions to the formation and integrity of the blood vessel wall within the microcirculation. Pericytes maintain vascular stability and homeostasis by promoting endothelial cell junctions and depositing extracellular matrix (ECM) components within the vascular basement membrane, among other vital functions. As their importance in sustaining microvessel health within various tissues and organs continues to emerge, so does their role in a number of pathological conditions including cancer, diabetic retinopathy, and neurological disorders. Here, we review vascular pericyte contributions to the development and remodeling of the microcirculation, with a focus on the local microenvironment during these processes. We discuss observations of their earliest involvement in vascular development and essential cues for their recruitment to the remodeling endothelium. Pericyte involvement in the angiogenic sprouting context is also considered with specific attention to crosstalk with endothelial cells such as through signaling regulation and ECM deposition. We also address specific aspects of the collective cell migration and dynamic interactions between pericytes and endothelial cells during angiogenic sprouting. Lastly, we discuss pericyte contributions to mechanisms underlying the transition from active vessel remodeling to the maturation and quiescence phase of vascular development.
-
Atherosclerosis-related cardiovascular diseases are a leading cause of mortality worldwide. Vascular smooth muscle cells (VSMCs) comprise the medial layer of the arterial wall and undergo phenotypic switching during atherosclerosis to a synthetic phenotype capable of proliferation and migration. The surrounding environment undergoes alterations in extracellular matrix (ECM) stiffness and composition in addition to an increase in addition to an increase in cholesterol content. Using an atherosclerotic murine model, we analyzed how the mechanics of VSMCs isolated from western diet fed apolipoprotein-E knockout (ApoE -/- ) and wild type (WT) mice were altered during atherosclerosis. Increased stiffness of ApoE -/- VSMCs correlated with a greater degree of stress fiber alignment as evidenced by atomic force microscopy (AFM)-generated force maps and stress fiber topography images. On type-1 collagen (COL1)-coated polyacrylamide (PA) gels of varying stiffness, WT VSMCs had higher adhesion forces to N-Cadherin (N-Cad) and COL1. ApoE -/- VSMC stiffness was significantly greater than WT cells with increased cell stiffness with increasing substrate stiffness for both ApoE -/- and WT VSMCs . In addition, ApoE -/- VSMCs showed an enhanced migration capability on COL1-coated substrates and a general decreasing trend in migration capacity with increasing substrate stiffness, correlating with the lower adhesion forces as compared to WT VSMCs. Altogether, these results demonstrate the potential contribution of the alteration in VSMC mechanics in the development of atherosclerosis.more » « less
-
more » « less
Abstract Glioblastoma multiforme (GBM) is the most lethal primary brain tumor characterized by high cellular and molecular heterogeneity, hypervascularization, and innate drug resistance. Cellular components and extracellular matrix (ECM) are the two primary sources of heterogeneity in GBM. Here, biomimetic tri‐regional GBM models with tumor regions, acellular ECM regions, and an endothelial region with regional stiffnesses patterned corresponding to the GBM stroma, pathological or normal brain parenchyma, and brain capillaries, are developed. Patient‐derived GBM cells, human endothelial cells, and hyaluronic acid derivatives are used to generate a species‐matched and biochemically relevant microenvironment. This in vitro study demonstrates that biophysical cues are involved in various tumor cell behaviors and angiogenic potentials and promote different molecular subtypes of GBM. The stiff models are enriched in the mesenchymal subtype, exhibit diffuse invasion of tumor cells, and induce protruding angiogenesis and higher drug resistance to temozolomide. Meanwhile, the soft models demonstrate enrichment in the classical subtype and support expansive cell growth. The three‐dimensional bioprinting technology utilized in this study enables rapid, flexible, and reproducible patient‐specific GBM modeling with biophysical heterogeneity that can be employed by future studies as a tunable system to interrogate GBM disease mechanisms and screen drug compounds.
-
Altered tissue mechanics is an important signature of invasive solid tumors. While the phenomena have been extensively studied by measuring the bulk rheology of the extracellular matrix (ECM) surrounding tumors, micromechanical remodeling at the cellular scale remains poorly understood. By combining holographic optical tweezers and confocal microscopy on in vitro tumor models, we show that the micromechanics of collagen ECM surrounding an invading tumor demonstrate directional anisotropy, spatial heterogeneity and significant variations in time as tumors invade. To test the cellular mechanisms of ECM micromechanical remodeling, we construct a simple computational model and verify its predictions with experiments. We find that collective force generation of a tumor stiffens the ECM and leads to anisotropic local mechanics such that the extension direction is more rigid than the compression direction. ECM degradation by cell-secreted matrix metalloproteinase softens the ECM, and active traction forces from individual disseminated cells re-stiffen the matrix. Together, these results identify plausible biophysical mechanisms responsible for the remodeled ECM micromechanics surrounding an invading tumor.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3389/fphys.2022.1016382
