Endothelial fluid shear stress sensing in vascular health and disease

Baeyens, Nicolas; Bandyopadhyay, Chirosree; Coon, Brian Bg; Yun, Sanguk; Schwartz, Martin A.

doi:10.1172/jci83083

Cited by 467 publications

(439 citation statements)

References 120 publications

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“…Fibronectin accumulation and production of IL6 (Figure 8) are early signs of endothelial inflammation. In particular, fibronectin accumulation regulates activation of mediators such as nuclear factor kappa B,40, 41 an established inducer of cytokines including IL6.…”

Section: Discussionmentioning

confidence: 99%

CD36 Deficiency Impairs the Small Intestinal Barrier and Induces Subclinical Inflammation in Mice

Cifarelli

Ivanov

Son

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims CD36 has immuno-metabolic actions and is abundant in the small intestine on epithelial, endothelial and immune cells. We examined the role of CD36 in gut homeostasis using mice null for CD36 (CD36KO) and with CD36 deletion specific to enterocytes (Ent-CD36KO) or endothelial cells (EC-CD36KO). Methods Intestinal morphology was evaluated using immunohistochemistry and electron microscopy (EM). Intestinal inflammation was determined from neutrophil infiltration and expression of cytokines, toll-like receptors and COX-2. Barrier integrity was assessed from circulating lipopolysaccharide (LPS) and dextran administered intragastrically. Epithelial permeability to luminal dextran was visualized using two photon microscopy. Results The small intestines of CD36KO mice fed a chow diet showed several abnormalities including extracellular matrix (ECM) accumulation with increased expression of ECM proteins, evidence of neutrophil infiltration, inflammation and compromised barrier function. EM showed shortened desmosomes with decreased desmocollin 2 expression. Systemically, leukocytosis and neutrophilia were present together with 80% reduction of anti-inflammatory Ly6Clow monocytes. Bone marrow transplants supported the primary contribution of non-hematopoietic cells to the inflammatory phenotype. Specific deletion of endothelial but not of enterocyte CD36 reproduced many of the gut phenotypes of germline CD36KO mice including fibronectin deposition, increased interleukin 6, neutrophil infiltration, desmosome shortening and impaired epithelial barrier function. Conclusions CD36 loss results in chronic neutrophil infiltration of the gut, impairs barrier integrity and systemically causes subclinical inflammation. Endothelial cell CD36 deletion reproduces the major intestinal phenotypes. The findings suggest an important role of the endothelium in etiology of gut inflammation and loss of epithelial barrier integrity.

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Section: Discussionmentioning

confidence: 99%

CD36 Deficiency Impairs the Small Intestinal Barrier and Induces Subclinical Inflammation in Mice

Cifarelli

Ivanov

Son

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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“…What role does impaired GTB play in disorders of kidney function and in the progression of chronic kidney disease? It is known that fluid shear stresses contribute to normal morpho-genesis and disease under pathological conditions in the cardiovascular system [3, 25, 31, 40, 41]. Thus, it will be important to define the roles of GTB under pathophysiological conditions in the kidney.…”

Section: Discussionmentioning

confidence: 99%

Regulation of glomerulotubular balance: flow-activated proximal tubule function

Wang

Weinbaum

Weinstein

2017

Pflugers Arch - Eur J Physiol

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The purpose of this review is to summarize our knowledge and understanding of the physiological importance and the mechanisms underlying flow-activated proximal tubule transport. Since the earliest micropuncture studies of mammalian proximal tubule, it has been recognized that tubular flow is an important regulator of sodium, potassium, and acid-base transport in the kidney. Increased fluid flow stimulates Na+ and HCO3− absorption in the proximal tubule via stimulation of Na/H-exchanger isoform 3 (NHE3) and H+-ATPase. In the proximal tubule, brush border microvilli are the major flow sensors, which experience changes in hydrodynamic drag and bending moment as luminal flow velocity changes and which transmit the force of altered flow to cytoskeletal structures within the cell. The signal to NHE3 depends upon the integrity of the actin cytoskeleton; the signal to the H+-ATPase depends upon microtubules. We have demonstrated that alterations in fluid drag impact tubule function by modulating ion transporter availability within the brush border membrane of the proximal tubule. Beyond that, there is evidence that transporter activity within the peritubular membrane is also modulated by luminal flow. Secondary messengers that regulate the flow-mediated tubule function have also been delineated. Dopamine blunts the responsiveness of proximal tubule transporters to changes in luminal flow velocity, while a DA1 antagonist increases flow sensitivity of solute reabsorption. IP3 receptor-mediated intracellular Ca2+ signaling is critical to transduction of microvillus drag. In this review, we summarize our findings of the regulatory mechanism of flow-mediated Na+ and HCO3− transport in the proximal tubule and review available information about flow sensing and regulatory mechanism of glomerulotubular balance.

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“…In the vascular system, endothelial cells are also exposed to hemodynamic forces resulting from hydrostatic pressure in vessels and blood flow 164 . VE-cadherin forms a mechanosensory complex with platelet endothelial cell adhesion molecule 1 (PECAM-1) along with VEGFR2 and VEGFR3 enabling the endothelium to sense changes in hemodynamics and thus activate a variety of signaling pathways 165, 166 (Figure 3).…”

Section: Mechanisms Of Ve-cadherin Cis- and Trans-interactionmentioning

confidence: 99%