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Review
. 2024 Jan 1;221(1):e20222008.
doi: 10.1084/jem.20222008. Epub 2023 Dec 5.

Mechanisms and functions of intestinal vascular specialization

Jeremiah Bernier-Latmani  1 , Alejandra González-Loyola  2 , Tatiana V Petrova  1   3
Affiliations
Review

Mechanisms and functions of intestinal vascular specialization

Jeremiah Bernier-Latmani et al. J Exp Med. .

Abstract

The intestinal vasculature has been studied for the last 100 years, and its essential role in absorbing and distributing ingested nutrients is well known. Recently, fascinating new insights into the organization, molecular mechanisms, and functions of intestinal vessels have emerged. These include maintenance of intestinal epithelial cell function, coping with microbiota-induced inflammatory pressure, recruiting gut-specific immune cells, and crosstalk with other organs. Intestinal function is also regulated at the systemic and cellular levels, such that the postprandial hyperemic response can direct up to 30% of systemic blood to gut vessels, while micron-sized endothelial cell fenestrations are necessary for nutrient uptake. In this review, we will highlight past discoveries made about intestinal vasculature in the context of new findings of molecular mechanisms underpinning gut function. Such comprehensive understanding of the system will pave the way to breakthroughs in nutrient uptake optimization, drug delivery efficiency, and treatment of human diseases.

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Conflict of interest statement

Disclosures: The authors declare no competing interests exist.

Figures

Figure 1.
Figure 1.
Organization of the GI tract and gut vasculature. (A) GI tract organization and contribution to systemic circulation. All intestine-derived blood flows through the portal vein and into the liver. Intestinal lymph drains to the MLNs before entering systemic blood circulation via the cisterna chyli and thoracic duct. The gut-to-brain connection through the nervous system is also depicted. (B) Epithelial cells are maintained by constant proliferation of crypt-housed stem cells, which differentiate upon migration to the villus to give rise to all differentiated cell types. Gradients of Wnt and Bmp ligands along the villus/crypt axis promote epithelial stemness and differentiation, respectively. BV, blood vessels; LV, lymphatic vessels. Enterocyte zonation is marked along villus axis. (C) Environmental factors such as nutrients, osmolarity, oxygen pressure, and microbiota-derived inflammatory molecules also form gradients along the villus/crypt axis. (D) Organization of the blood vasculature along the villus/crypt axis. Villus blood capillaries are VEGFA dependent (due to villus tip hypoxia) and display signs of angiogenesis (filopodia), while crypt capillaries reside in normoxic conditions and are VEGFA independent (BECs, blood endothelial cells). (E) Organization of the lymphatic vasculature along the villus/crypt axis. Villus-housed blind-ended lymphatic capillaries (lacteals) display signs of lymphangiogenesis such as filopodia and LEC proliferation and are ensheathed by villus SMCs. Crypt lymphatic capillaries do not display filopodia and crypt LECs rarely proliferate. All intestinal lymphatic capillaries, except for those with filopodia, display permeable button cell–cell junctions distinguishing them from mesenteric lymphatic collecting vessels, which display zipper cell–cell junctions, valves, and SMC coverage.
Figure 2.
Figure 2.
Functional roles for intestinal vasculature in promoting nutrient absorption. (A) Villus blood capillary endothelial cells display small pores, fenestrations, which promote rapid absorption of nutrients transported through the epithelium. High levels of villus VEGFA (from epithelial cells and fibroblasts) promote endothelial fenestration. VEGFA signaling is highest at the villus tip, and VEGFA protein and fenestrations are polarized to the epithelial side of endothelial cells (ECs). VEGFA blockade restricts fenestrations and EC nuclear polarization, making vessels less permeable. VTTs also promote polarized EC fenestration. These fibroblasts uniquely express the metalloprotease ADAMTS18, which degrades fibronectin, thus constraining VEGFA to the epithelial side of ECs. In the absence of VTTs or ADAMTS18, villus tip fibronectin accumulates and spreads bound VEGFA, thereby promoting widespread vessel fenestration and leakiness. (B) Lacteal cell–cell junction status controls dietary fat absorption. Enterocytes package dietary fat into lipoprotein particles called chylomicrons, which are size excluded from blood capillaries. Chylomicrons enter the lymphatic system through open button junctions between lacteal LECs. Increased VEGFC/VEGFR3 or VEGFA/VEGFR2 signaling or loss of Notch signaling leads to zippering of LEC junctions and decreased chylomicron absorption.
Figure 3.
Figure 3.
Role of intestinal vasculatures in maintaining epithelial homeostasis. (A) Intestinal villi are hypoxic, leading to VEGFA expression and the presence of VEGFA-dependent blood capillaries. In contrast, crypts are normoxic, O2 is necessary for stem cell maintenance, and blood vessels are VEGFA independent. Rather, crypt vessel expansion depends on apelin (Apln) signaling to promote intravessel endothelial cell (EC) migration from the villus to the crypt. During pathological crypt expansion, e.g., following epithelial APC loss-of-function (initiating mutation in colon cancer), blood capillaries expand in a VEGFA-independent manner, allowing stem cell proliferation and migration. In the absence of Apln, crypt vessels lack endothelial cells to maintain vessel patency resulting in crypt hypoxia and epithelial progenitor cell death. (B) Crypt lymphatics promote emergency stem cell maintenance. The Wnt signaling potentiator RSPO3 is produced by crypt lymphatics and fibroblasts, where it promotes stem cell maintenance, especially during intestinal injury. The secreted protein reelin is also expressed by crypt lymphatics and contributes to epithelial regrowth after injury by binding its receptors VLDLR, ITGB1, and LRP8. ISC, intestinal stem cell.
Figure 4.
Figure 4.
Roles for the intestinal vasculatures in immune cell trafficking and response to gut microbiota. (A) Immune cell transport by intestinal blood vessels. Post-capillary HEV-like vessels present in each small intestinal villus. HEVs in PPs, GALT, express addressin proteins that enable gut-specific immune cell recruitment. HEVs and villus HEV-like vessels express MADCAM1 and ICAM1, which bind α4β7 and αLβ2 on lymphocytes, respectively. ST6GAL1 codes for a glycan siaylating protein, which produces the BMAd. Additionally, enterocytes express CCL25 chemokine promoting extravasation of CCR9-expressing lymphocytes in the gut. (B) Developmental control of mucosal addressins. Embryonic HEVs of PLN and MLN express MADCAM1, which is restricted postnatally to the GI tract HEVs and HEV-like villus vessels. This is mediated in part by cooperation between the transcription factors NKX2.3 and COUP-TFII, which also promote expression of the gene encoding the BMAd-generating enzyme ST6GAL1. (C) Immune cell transport by intestinal lymphatics. Lymphatic capillaries recruit CCR7+ immune cells through secretion of CCL21. A major population that is trafficked from the gut are CD103+ DCs, which carry antigens from a variety of sources. Most B cells are recirculated via PP lymphatic vessels (Reboldi and Cyster, 2016). While DC-carried food antigens are more prevalent in the duodenum, microbiota-derived antigens are found in ileum DCs. Treg, regulatory T cell. (D) Intestinal vessels display specialized mechanisms to resist microbiota-driven inflammation. These include resistance to TNF signaling (TAK1, CASP8), modulation of permeability in response to infection, and maintenance of lymph outflow of immune cells and chylomicrons. PAMP, pathogen-associated molecular pattern; DAMP, damage-associated molecular pattern; EC, endothelial cell.
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