Abstract
The vasculature ensures optimal delivery of nutrients and oxygen throughout the body, and to achieve this function it must continually adapt to varying tissue demands. Newly formed vascular plexuses during development are immature and require dynamic remodeling to generate well-patterned functional networks. This is achieved by remodeling of the capillaries preserving those which are functional and eliminating other ones. A balanced and dynamically regulated capillary remodeling will therefore ensure optimal distribution of blood and nutrients to the tissues. This is particularly important in pathological contexts in which deficient or excessive vascular remodeling may worsen tissue perfusion and hamper tissue repair. Blood flow is a major determinant of microvascular reshaping since capillaries are pruned when relatively less perfused and they split when exposed to high flow in order to shape the microvascular network for optimal tissue perfusion and oxygenation. The molecular machinery underlying blood flow sensing by endothelial cells is being deciphered, but much less is known about how this translates into endothelial cell responses as alignment, polarization and directed migration to drive capillary remodeling, particularly in vivo. Part of this knowledge is theoretical from computational models since blood flow hemodynamics are not easily recapitulated by in vitro or ex vivo approaches. Moreover, these events are difficult to visualize in vivo due to their infrequency and briefness. Studies had been limited to postnatal mouse retina and vascular beds in zebrafish but new tools as advanced microscopy and image analysis are strengthening our understanding of capillary remodeling. In this review we introduce the concept of remodeling of the microvasculature and its relevance in physiology and pathology. We summarize the current knowledge on the mechanisms contributing to capillary regression and to capillary splitting highlighting the key role of blood flow to orchestrate these processes. Finally, we comment the potential and possibilities that microfluidics offers to this field. Since capillary remodeling mechanisms are often reactivated in prevalent pathologies as cancer and cardiovascular disease, all this knowledge could be eventually used to improve the functionality of capillary networks in diseased tissues and promote their repair.
Highlights
Specialty section: This article was submitted to Vascular Physiology, a section of the journal Frontiers in Physiology
Following a top-down approach (Hesh et al, 2019), we propose two prototypes of hybrid devices that on one hand are inspired on real microvascular networks in which capillary pruning and splitting occurs (Figure 3A,B), mimicking their preferential H and Y geometries; and on the other, they incorporate predicted shear stress values and spatiotemporal gradients, as discussed along this review, whose tuning and dynamics could only be recapitulated in these systems (Figure 3C)
The small GTPase Rac1 has been involved in capillary pruning in the brain zebrafish microvasculature and it is tempting to speculate that Rac1 inhibitors may help prevent excessive brain capillary pruning associated for example with aging or Alzheimer’s disease (Garkavtsev et al, 2011; Chen et al, 2012)
Summary
Specialty section: This article was submitted to Vascular Physiology, a section of the journal Frontiers in Physiology. In the context of capillary pruning in the mouse postnatal retina, computational modeling studies stated that soluble signals such as VEGF (induced in low perfused regions) will complement blood flow actions in the vascular regression process (Watson et al, 2012).
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