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Review
. 2023 May 23;80(6):162.
doi: 10.1007/s00018-023-04801-z.

The role of blood flow in vessel remodeling and its regulatory mechanism during developmental angiogenesis

Lin Wen  1 , Wenhua Yan  1 , Li Zhu  2 , Chaojun Tang  3 , Guixue Wang  4   5
Affiliations
Review

The role of blood flow in vessel remodeling and its regulatory mechanism during developmental angiogenesis

Lin Wen et al. Cell Mol Life Sci. .

Abstract

Vessel remodeling is essential for a functional and mature vascular network. According to the difference in endothelial cell (EC) behavior, we classified vessel remodeling into vessel pruning, vessel regression and vessel fusion. Vessel remodeling has been proven in various organs and species, such as the brain vasculature, subintestinal veins (SIVs), and caudal vein (CV) in zebrafish and yolk sac vessels, retina, and hyaloid vessels in mice. ECs and periendothelial cells (such as pericytes and astrocytes) contribute to vessel remodeling. EC junction remodeling and actin cytoskeleton dynamic rearrangement are indispensable for vessel pruning. More importantly, blood flow has a vital role in vessel remodeling. In recent studies, several mechanosensors, such as integrins, platelet endothelial cell adhesion molecule-1 (PECAM-1)/vascular endothelial cell (VE-cadherin)/vascular endothelial growth factor receptor 2 (VEGFR2) complex, and notch1, have been shown to contribute to mechanotransduction and vessel remodeling. In this review, we highlight the current knowledge of vessel remodeling in mouse and zebrafish models. We further underline the contribution of cellular behavior and periendothelial cells to vessel remodeling. Finally, we discuss the mechanosensory complex in ECs and the molecular mechanisms responsible for vessel remodeling.

Keywords: EC rearrangement; Hemodynamics; Vessel pruning; Wnt signaling; Zebrafish.

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Conflict of interest statement

The authors have no relevant financial interests to disclose.

Figures

Fig. 1
Fig. 1
Vessel fusion contributes to engaging the vessel diameter. a Vessel fusion in the cultured mouse embryo. Blood enters the vascular plexus through the vitelline artery to the distal capillaries and is ultimately collected by the vitelline vein at E8.5. Vessel fusion (marked with circles) occurs in the proximal vessels that are exposed to high blood flow, resulting in a rapid change in vessel diameter. Vessel hierarchy is established through vessel fusion by E9.0–9.5, resulting in different flow velocity distributions in arteries, capillaries and veins. b Vessel fusion is mediated by the redistribution of ECs. Figure a adapted from Ryan et al. [6]
Fig. 2
Fig. 2
Vessel pruning in the mouse retinas. a Fluorescence immunohistochemistry of the mouse retinas using isolectin B4 (IB4, grey) to show the vasculature. The process of angiogenesis and vessel pruning in the mouse retina from P6 to P18. The vessel density reaches a pink at P10. Vessel pruning contributes to decreasing the vessel density from P10 to P18. Scale bar 200 μm. b Fluorescence immunohistochemistry of the mouse retinas using anti-collagen type IV (Col. IV, green) and IB4 (red) to visualize vessel pruning at P10. Arrowheads indicate the segments undergoing vessel pruning, characterized by IB4-/Col. IV + antibody staining. Scale bar 200 μm
Fig. 3
Fig. 3
Anastomosis and vessel pruning events in the zebrafish model. a The process of anastomosis and vessel pruning in zebrafish vasculature. The central panel shows an overview of the zebrafish vascular beds. Sprouting and anastomosis have been studied in the palatocerebral artery (PLA), the communicating vessel (CMV) and the segmental arteries (aISV). Vessel pruning has been studied in the midbrain vasculature, the subintestinal vein (SIV), the segmental veins (vISV) and the caudal vein (CV). Figure a adapted from Charles et al. [34]. The process of zebrafish CV pruning is mediated by EC rearrangement, which includes the stages of selection pruning segment (b), cell migration (c), stenosis (d), retraction (e) and close-up (f). b The diameters of the lower branch and the upper branch are the same at the beginning of vessel pruning. c, d The ECs marked with blue and green migrate against the blood flow, resulting in vessel stenosis at the lower branch. e, f The ECs marked with blue and green migrate into the adjacent vessel, finishing the pruning of the lower branch. The arrow indicates the direction of blood flow. The rearrangement of ECs during vessel pruning is marked with blue and green. The arrows in (c, f) indicate the direction of EC migration. The arrows in (d, e) indicate vessel stenosis. Figure b–f adapted from Wen et al. [28]
Fig. 4
Fig. 4
The role of blood flow during vessel pruning, in which the segment with lower blood flow is pruned. a The diameter of the upper branch and the lower branch is the same before vessel pruning, while the blood flow velocity of the lower branch is lower than that of the upper branch. b Vessel stenosis occurs at the lower branch with low blood flow. c No blood perfusion in the lower branch. d, e The lower branch is pruned, while the upper branch remains
Fig. 5
Fig. 5
Mechanosensors regulate vessel remodeling, including integrin signaling, VE-cadherin, VEGFR2/3, PECAM-1 complex and Notch1 signaling. Integrins interact with Thbs 1 to promote YAP nuclear translocation and regulate vessel remodeling by promoting cell migration, junctions and actin cytoskeleton rearrangement. Flow shear stress (FSS)-induced ERK1/2 activation and Akt phosphorylation depend on integrin binding to extracellular matrix (ECM) proteins. The combination of integrins and ECM proteins induces a transient inhibition of Rho and the activation of downstream JNKS, which is necessary for cytoskeletal alignment in the direction of flow. The mechanosensory complex, PECAM-1-VE-Cadherin-VEGFRs, activates the PI3K-Akt pathway to promote cell migration. PECAM-1 directly senses mechanical force and then activates Src, and VE-cadherin binds with β-catenin and VEGFR2/3 to activate downstream P13K and integrin. The NOTCH1 mechanosensory complex senses FSS and regulates junctions and actin dynamics, which includes the processes of (i) FSS-induced endocytosis of DLL4; (ii) cleavage of NOTCH1 to expose the transcellular domain (TCD); and (iii) binding to the LAR with VE-cadherin and TRIO to activate the downstream target RAC1
Fig. 6
Fig. 6
Role of Wnt signaling in vessel remodeling. Non-canonical Wnt ligands activate Wnt/Ca2+ signaling and regulate vessel remodeling at the transcriptional level of apoptosis- and proliferation-related genes. Evi/Wls/R-spondin3 (Rspo3) activate non-canonical WNT/calcium signaling at the level of NFAT1 by downregulating Rnf213, Usp18, and Trim30α, which balance the level of cell survival genes to regulate vessel pruning in the retina. Canonical Wnt signaling receptors, coreceptors and ligands cooperate with Dll4/Notch signaling, and pericytes secrete Ang II to balance the progress of vessel remodeling. Canonical Norrin/Fz4/Lrp5/6 accelerate β-catenin nuclear translocation and control the transcription of Cyclin D1 or Myc-Cdkn1a to regulate cell survival. The negative regulatory factor Apcdd1 controls vessel density transiently in retina during P10-12. Dll4/Notch signaling stimulates expression of Nrarp and contributes to canonical Wnt signaling by interacting with Lef1/Ctnnb1. Ang2 produced by pericytes has a dual identity in the regulation of cell death. On the one hand, Ang2 suppresses Akt to permit cell death. On the other hand, Ang2 promotes the secretion of Wnt7b by macrophages to activate the Wnt/β-catenin pathway, which inhibits cell death by promoting cell cycle entry to regulate hyaloid regression
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