Introduction
The vasculature is crucial in efficiently delivering nutrients and oxygen throughout the body, continually adapting to varying tissue demands. During development, newly formed vascular plexuses are immature, requiring dynamic remodeling to create well-patterned functional networks. Capillary remodeling involves preserving functional capillaries and eliminating others, ensuring a balanced and dynamically regulated process for optimal blood and nutrient distribution. This is particularly significant in pathological conditions, where improper vascular remodeling can negatively impact tissue perfusion and repair.
What Is Meant by Capillary Pruning Couples Tissue Perfusion?
In the developmental stages of an organism, primitive vascular networks undergo refinement for proper function. Capillary pruning, a crucial process in this remodeling, involves selectively eliminating poorly functioning vascular segments to promote the formation of hierarchical networks.
Blood flow is a key factor in microvascular reshaping, with capillaries being pruned in less perfused areas and splitting in response to high flow to optimize tissue perfusion. While the molecular machinery behind blood flow sensing is being unraveled, understanding how it translates into endothelial cell responses for capillary remodeling, especially in vivo, remains challenging.
Recent advancements in confocal microscopy and image analysis have shaped the current model of capillary pruning. This model emphasizes blood flow as the primary determinant, with endothelial cells migrating against the flow from poorly perfused vessels towards adjacent highly perfused vessels. This phenomenon is observed in the yolk sac, the 2D stereotype vasculature of the postnatal mouse retina, and zebrafish brain vessels, where the small GTPase Rac1 appears to play a significant role.
Capillary pruning is proposed to optimize blood flow distribution, ensuring efficient transport of oxygen and nutrients from large vessels to distal territories. Computational stimulation in the postnatal retina vasculature supports this concept, but experimental testing has remained challenging. Excessive capillary pruning appears to reduce vascular density after conditions such as myocardial infarction or Alzheimer’s disease and is associated with aging and loss of neuronal activity in the brain.
How Does Microvascular Remodeling Work?
The microvasculature continually adapts to tissue metabolic demands through functional and structural adjustments. This involves the dynamic remodeling of capillaries, preserving and expanding functional ones while eliminating redundant or inefficient ones.
Two primary processes govern microvascular reshaping in various organs and tissues during growth and development:
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Capillary pruning, or regression, involves eliminating non-functional capillaries to form a hierarchically branched functional network.
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Duplication of highly perfused capillaries, leading to rapid expansion of the microvasculature. Duplication can occur through intussusceptive angiogenesis, where a large lumen within a sinus divides or by splitting in tubular capillaries.
Capillary regression events occur in diverse contexts, ranging from embryonic stages in the chicken yolk sac and limb embryo to postnatal stages in the mouse retina. Regression is associated with optimizing blood flow networks and eliminating unnecessary tissue, as seen in hyaloid regression after birth or post-lactation mammary gland involution.
Capillary duplication, observed in lung, heart, intestine, liver, or kidney tissues, contributes to microvasculature expansion during embryonic and organ development. These mechanisms are often reactivated or impaired in prevalent pathologies, leading to dysfunctional microvasculature that exacerbates damage and hinders tissue repair. Altered capillary pruning is observed in conditions like tumors, myocardial infarction, hypertension, age-related neurodegeneration, and Alzheimer’s disease. Capillary splitting is noted in inflammatory bowel disease, tumors, lung dysplasia of prematurity, and other syndromes, contributing to disease progression. Impaired endothelial cell responses in microvascular remodeling can also lead to the persistence of arteriovenous shunts, forming the basis for arteriovenous malformations (AVM).
Capillary remodeling events are dynamic, unfolding within hours to a few days, involving active endothelial cell arrangements and rapid morphological changes in the microvasculature. The current model for capillary pruning suggests a multi-staged process initiated by the blood flow-driven selection of the regressing vascular branch, leading to morphological alterations, endothelial cell retraction, migration, and integration into the adjacent vessel. This results in an ‘empathy sleeve’ considered a hallmark of vessel regression. Understanding the dynamics of capillary pruning and duplication is crucial for comprehending vascular reshaping mechanisms and their implications for tissue development and pathology.
What Is the Mechanism of Blood Flow in Capillary Pruning?
Shear stress sensed by endothelial cells initiates diverse cellular responses, ultimately leading to capillary remodeling in vivo. In vitro studies show that endothelial cells elongate and align in a shear stress-dependent manner, with longer exposure times needed for alignment. Higher laminar flow and shear stress increase polarization and migration against the flow direction. However, the sequential nature of these responses depends on factors like endothelial cell type, the onset of blood flow, and process kinetics.
New insights in capillary remodeling emphasize the significance of molecular pathways involved in endothelial cell sensing of blood flow or shear stress and subsequent transduction into extracellular and intracellular gradients. Mechanosensors like Piezo1, Yap/Taz, and Kir2.1 respond rapidly to shear stress, acting as upstream regulators for early endothelial cell responses crucial for capillary pruning. Various pathways, including non-canonical Wnt, BMP, and Notch signaling, contribute to the complex regulation of capillary remodeling.
The mechanisms underlying capillary splitting must be understood, lacking an optimal in vitro model. Nitric oxide, regulated by eNOS, plays a vital role in endothelial cell rearrangements necessary for capillary splitting. Additional factors like VEGF, PDGFB, EphrinB2/EphB4 pathways, RECK, and Notch are implicated in capillary splitting regulation. Potential cues involve endothelial cell junction components, basement membrane interactions, and the actin cytoskeleton, contributing to the intricate regulatory network governing capillary remodeling.
Conclusion
Tissues undergo continuous adjustments to meet their oxygen and nutrient demands, relying on microvascular adaptation through capillary remodeling. This dynamic process involves pruning to eliminate poorly functional segments and splitting to duplicate segments, optimizing blood flow distribution.
Dysregulated capillary remodeling can lead to inadequate tissue perfusion, damaging or hindering repair. Understanding these mechanisms and exploring strategies to prevent diseases and promote tissue repair.
Microvascular remodeling intricacies also impact the formation of arteriovenous shunts. Recent findings highlighting endoglin as a key regulator in preventing arteriovenous malformations offer insights into the mechanistic links between endothelial cell responses to blood flow and associated diseases.
