Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research)


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PKD1 is a amino acids long transmembrane protein with 11 membrane-spanning domains. Its long extracellular N-terminus has a mechanosensory function, while its short intracellular C-terminus is involved in intracellular signaling and interaction with PKD2 [ 34 , 35 ]. PKD1 has been shown to mediate fluid-shear sensing in epithelial and endothelial cells [ 9 , 36 ].

This turns on a signaling cascade leading to the production of NO [ 9 , 38 , 40 ]. Interestingly, mutations or deletion of polaris seem to affect the structural integrity of cilia through the PKD1 and PKD2 mislocalization, which remain concentrated at the basal body [ 9 , 29 , 32 , 41 ]. Together these findings evidence that polaris mediates the PKD1 and PKD2 primary cilium localization, implying a polaris cilium sensory function regulation. In order to achieve a proper fluid-shear sensing by endothelial cells and an adequate response, all three components, PKD1, PKD2 and polaris, are thus indispensable.

This particular pathway is summarized in Figure 2. Mechanotransduction of FSS at the endothelial primary cilium. Calcium binds to ryanodine receptors and an efflux of intracellular organelle calcium. Figure reproduced with permission [38].


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The works of AbouAlaiwi et al. The same effect was shown after blocking calcium-dependent mechanisms of NO production using calphostin C as an inhibitor of protein kinase C PKC or W7 as antagonist of calmodulin. Changes in fluid patterns generate differential biomechanical forces, which lead to alteration of cilia function or structure [ 2 ]. Indeed, almost all blood vessels possess cilia [ 4 , 23 ].

Particularly, arteries with low FSS or high fluid turbulence have cilia [ 2 ]. A prolonged exposure of endothelial cells to high FSS induces the disassembly of cilia [ 28 ] and inactivation of PKD1 by proteolytic cleavage [ 9 ], suggesting that primary cilia may not be required only to sense high shear stress [ 2 ]. The process of disassembly observed here involves the termination of IFT and the inability of the oldest centriole to maintain or initiate the assembly of primary cilia under laminar shear stress [ 28 ].

The disassembly of cilia parallels a major rearrangement of the cytoskeleton and an increase of acetylation of MT [ 18 , 44 ]. In the renal system, tubular flow and ROS act as potent modulators of epithelial kidney cell phenotype also by affecting the organization of the cytoskeleton and the brush border, changing cell polarity and modifying various cellular functions such as solute reabsorption and extracellular matrix remodeling [ 17 ].

Under oxidative stress, ROS directly induce the breakdown of the cell cytoskeleton, activate various cell death-associated signals and regulate elongation, shortening and release of cilia [ 45 ]. The mechanism and implications of this regulation are still unclear. Several sources of ROS have been extensively described in the literature, in which the nicotidamine adenine dinucleotide phosphate NADP oxidase Nox has been described as one of the main cellular sources of ROS generation in endothelial cells under FSS [ 47 ]. Flow patterns and the magnitude of shear determine the amount of ROS produced by endothelial cells, usually an irregular flow pattern disturbed or oscillatory producing higher levels of ROS than a regular flow pattern steady laminar or pulsatile [ 48 ].

ROS production is closely linked to NO generation: elevated levels of ROS lead to low NO bioavailability, as is often observed in endothelial cells exposed to irregular flow patterns [ 48 ]. NO can also take part in redox signaling by modifying proteins and lipids via cysteine S-nitrosation and fatty acid nitration, respectively [ 51 ], in this respect affecting the regulation of the vascular system [ 52 ].

Shear Stress and Endothelium Derived Relaxation Factor Part 1

Information related to primary cilium and free radical signaling emerges mainly from kidney research area. However, how ROS can regulate this mechanosensory organelle is not well described in the literature [ 17 , 30 , 53 ].

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It is known that renal primary cilia protrude from the epithelial cell surface into the lumen detecting fluid flow and responding to diverse stimuli [ 12 ]. Indeed, several reports show that an alteration of primary cilia length is associated with acute and chronic kidney disease [ 16 ]. Information about primary cilia acting as an upstream regulator of ROS comes primarily from in vitro experiments, in which immortalized macula densa cell line MMDD1 exposed to an increment in shear stress shows augmented NO production, this effect was blunted by silencing polaris protein in primary cilia using si-RNA methodology [ 54 ].

In addition, in isolated perfused juxtaglomerular apparatus preparations incubated with the diuretic furosemide an inhibitor of Na-K-Cl cotransporter , an increase in tubular flow-induced NO production was observed. Therefore, these results indicate that the primary cilium acts as a mechanosensory organelle for FSS inside the nephron tubule via NO. As presented by Kim et al. Concomitantly, they also showed that MnTMPyP decrease oxidative stress and recover nephron tubule morphology, indicating that the ROS signals are an integral part of cilium length regulation.

In addition, cultured kidney cells treated with H 2 O 2 released a ciliary fragment into the extracellular medium. MnTMPyP treatment inhibited this deciliation process [ 17 , 53 ]. Moreover, the extracellular signal-regulated kinase ERK inhibitor U blocked the cilium elongation of normal and H 2 O 2 -treated cells [ 53 ].

Taken together, these observations show that primary cilia length can be regulated, at least in part, by H 2 O 2 through an ERK-dependent pathway. In particular, transient hepatic ischemia caused functional and histological kidney damage, including brush border loss of tubular epithelial cells and tubule atrophy. These data confirm that free radical species can modulate the primary cilium length, at least in the kidney, but the mechanism and functional implications of such modulation remain unclear.

Sensing Fluid-Shear Stress in the Endothelial System with a Special Emphasis on the Primary Cilium

Activation of VEGFRs has been implicated in several vascular functions, including angiogenesis, vascular tone regulation and endothelial cell survival, among others [ 59 , 60 , 61 ]. Jin et al. Despite these evidences, as far as we known there is no information related to VEGFRs present in the primary cilium as potential regulator of FSS sensing.

VEGF can also bind to neuropilins NRP , a family of transmembrane glycoproteins that play key role in axonal guidance, angiogenesis, tumorigenesis and immunological response [ 65 ].


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In turn, semaphorins are a class of secreted and membrane proteins that were originally identified as axonal growth cone guidance molecules. Genetic studies in mice have confirmed that NRPs are key components of vasculogenesis, angiogenesis and lymphangiogenesis [ 65 , 66 ]. Limited information about the localization of NRP in primary cilium is available. Before presenting those evidences, we should give some information about hedgehog HH signaling.

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Briefly, HH signaling is essential for tissue patterning and organ formation during embryonic and postnatal development, as well as in cancer development and tissue homeostasis renewal and repair in adult animals [ 68 ]. The HH pathway acts via activation of transcriptional effectors, such as the glioblastoma Gli proteins, a family of transcription factors whose target genes remain enigmatic.

The Gli protein family includes Gli1, Gli2 and Gli3 [ 69 ]. Referring to the primary cilium, studies conducted by Pinskey et al. Interestingly, the authors found that a conserved 12 amino acid region of the NRP1 cytoplasmic domain between amino acids and is responsible for the HH-signal promotion. Considering that an intact primary cilium is a main component of the HH signaling, they also looked for the localization of NRP1 in this subcellular compartment and showed the unique evidence until now about the localization of NRP1, but not NRP2, in the primary cilium [ 68 ].

Despite the fact that the localization of NRP1 in the primary cilium was not required for HH signaling promotion, it is intriguing why NRP1 is present in primary cilium and what would be its physiological relevance there. Still more questions than answers emerge and more investigation is required to lighten these intriguing possibilities. The signaling pathway starts with the activation of a family of membrane receptors.

Briefly, adenosine receptor or P1 family includes at least four members of G-protein-coupled receptor subtypes identified as A 1 , A 2A , A 2B and A 3. ATP is released by almost all cell types after gentle mechanical stimulation and acts in an autocrine or paracrine manner [ 72 ].

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Living cells under stressful conditions i. Interestingly, purinergic signaling parallel to flow sensor activity of the primary cilium [ 73 ]. Purinergic signaling associated with flow sensing was detected in several structures such as kidney tubules [ 20 ], intrahepatic bile ducts [ 74 , 75 ], endothelial cells [ 31 ], among other lining cells. Therefore, deflection of the primary cilium has been related with ATP release leading to autocrine or paracrine activation of purinergic receptors.

The relationship between ATP, purinergic signaling and primary cilium has been studied in the kidney tubular system [ 73 ].

The same experiments were also performed in renal tubules from mice lacking P2Y 2 receptors or cells lacking the primary cilium. In those experiments, the response to tubular flow was markedly reduced only in those cells lacking the P2Y 2 [ 76 ]. These results strongly suggested that tubular flow triggers ATP release, followed by auto- and paracrine activation of epithelial P2 receptors. However, a direct link to the primary cilium could not be established in these experiments. Despite that, information regarding how purinergic signaling can be associated or not to function of primary cilia is missing.

As indicated above, the relevance of the primary cilium function has been well established in the kidney, as evidenced in polycystic kidney disease [ 37 , 77 , 78 ]. Physiologically, urinary flow through the nephron is a highly variable process.

Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research) Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research)
Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research) Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research)
Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research) Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research)
Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research) Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research)
Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research) Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research)
Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research) Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research)
Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research) Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research)
Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research) Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research)
Mechanical Forces and the Endothelium: 6 (Endothelial Cell Research)

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