Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

Billaud, Marie; Lohman, Alexander W.; Johnstone, Scott R.; Biwer, Lauren A; Mutchler, Stephanie; Isakson, Brant E.

doi:10.1124/pr.112.007351

Cited by 98 publications

(86 citation statements)

References 879 publications

(1,017 reference statements)

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“…Meanwhile, the diffusion of EDNO generated at the MEJ to the overlying VSMC is regulated by the redox status of iron in Hba that is richly expressed at the MEJ. This mechanism has not been explored in the pulmonary vasculature (10). Regarding the EV-mediated interaction between ECs and VSMCs, available evidence supports the notion that they may be critically involved in the pathobiology of PH.…”

Section: Discussionmentioning

confidence: 94%

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Endothelial and Smooth Muscle Cell Interactions in the Pathobiology of Pulmonary Hypertension

Gao

Chen

Raj

2016

Am J Respir Cell Mol Biol

115

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In the pulmonary vasculature, the endothelial and smooth muscle cells are two key cell types that play a major role in the pathobiology of pulmonary vascular disease and pulmonary hypertension. The normal interactions between these two cell types are important for the homeostasis of the pulmonary circulation, and any aberrant interaction between them may lead to various disease states including pulmonary vascular remodeling and pulmonary hypertension. It is well recognized that the endothelial cell can regulate the function of the underlying smooth muscle cell by releasing various bioactive agents such as nitric oxide and endothelin-1. In addition to such paracrine regulation, other mechanisms exist by which there is cross-talk between these two cell types, including communication via the myoendothelial injunctions and information transfer via extracellular vesicles. Emerging evidence suggests that these nonparacrine mechanisms play an important role in the regulation of pulmonary vascular tone and the determination of cell phenotype and that they are critically involved in the pathobiology of pulmonary hypertension.Keywords: paracrine; myoendothelial injunction; microvesicles; vasoconstriction; vascular remodelingIn the pulmonary vasculature, endothelial cells (ECs) and smooth muscle cells (SMCs) are the key cell types involved in the regulation of vessel diameter in most of the pulmonary vascular tree and thereby they regulate pulmonary arterial pressure and total vascular resistance. ECs, which are strategically located as the innermost layer of the blood vessel and are in contact with the circulating blood, exert a delicate and constant influence on the underlying vascular smooth muscle cells (VSMCs). It is well recognized that the regulation of pulmonary vasoreactivity by the endothelium is predominantly accomplished by paracrine signaling through the release of various vasoactive agents such as nitric oxide (NO), endothelin-1 (ET-1) (1-3), and others (4-8). However, there is increasing evidence that the relationship between the EC and the SMC is not a simple one-way interaction from the endothelium to the SMC; rather, there are complicated interactions between them (9-11). Moreover, the communication patterns are not limited to paracrine signaling; cross-talk through myoendothelial gap junctions (MEJs), extracellular vesicles (EVs), and other mechanisms is critically involved (12)(13)(14)(15)(16)(17)(18)(19)(20). These mechanisms operate in a complicated but co-ordinated manner to maintain the homeostasis of the pulmonary circulation. Under pathological conditions, the interaction between ECs and VSMCs may be chronically altered so that a sustained increase in vasocontractility and abnormal vascular proliferation develops, which leads to high pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy, and the clinical condition, pulmonary hypertension (PH) (1,(21)(22)(23)(24). This article discusses the recent progress in our knowledge of the interactions between ECs and SMCs thr...

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Section: Discussionmentioning

confidence: 94%

“…MEJs have been observed in several species and in many vascular beds, including the pulmonary vasculature (13,(90)(91)(92). There are more numerous MEJs in smaller-than in larger-diameter arteries (10,13,93). The more abundant expression of MEJs would facilitate electronic signals propagating between EC and SMC.…”

Section: Myoendothelial Junction Mechanismsmentioning

confidence: 99%

Endothelial and Smooth Muscle Cell Interactions in the Pathobiology of Pulmonary Hypertension

Gao

Chen

Raj

2016

Am J Respir Cell Mol Biol

115

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“…Because the sinoatrial and atrio-ventricular nodes are very concentrated in calcium channels, calcium increases are very prevalent in these regions and causes the increased conduction through the AV node. In addition, calcium channels are present in smooth muscles lining blood vessels [108]. Patients with a history of hypertension have increased intracellular calcium levels and may be on hypertension medication such as the calcium channel blockers nifedipine, amlodipine, diltiazem, or verapamil [109].…”

Section: Glucopsychosine As a Novel Therapy For Amlmentioning

confidence: 99%

Glucopsychosine increases cytosolic calcium to induce calpain-mediated apoptosis of acute myeloid leukemia cells

Angka¹,

Lee²,

Rota³

et al. 2014

Cancer Letters

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“…For our purposes, we have defined a restricted cellular space as an anatomical area of the cell that is distinctly separate from the cytoplasm of the rest of the cell, usually encompassing a small projection of a cell or nanometer domains between organelle membranes. These cellular microdomains are identified by expression of specific proteins, receptors and/or ion channels [73][74][75] . Numerous examples can be found throughout an organism; we will focus on dendritic spines of neurons 76 , plasma membrane-sarcoplasmic reticulum (SR) junctions in myocytes 77 , and myoendothelial junctions in endothelial cells 73 .…”

Section: Introductionmentioning

confidence: 99%

“…These cellular microdomains are identified by expression of specific proteins, receptors and/or ion channels [73][74][75] . Numerous examples can be found throughout an organism; we will focus on dendritic spines of neurons 76 , plasma membrane-sarcoplasmic reticulum (SR) junctions in myocytes 77 , and myoendothelial junctions in endothelial cells 73 . The ER is further able to form unique signaling microdomains in close contact with Golgi, mitochondrial, and plasma membranes, which are integral to calcium and lipid homeostasis ( Figure 1C, D).…”

Section: Introductionmentioning

confidence: 99%

Signaling Microdomains within the Myoendothelial Junction

Biwer

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Communication between endothelial and smooth muscle cells is critical to maintain homeostatic vascular tone and blood pressure. In resistance arteries, the cells make direct cytoplasmic contact via cellular extensions that project through the thin extracellular matrix of the internal elastic lamina that separates them. These structures are termed myoendothelial junctions (MEJ). There are a number of proteins and signaling processes localized to this part of the arterial wall that regulate bi-directional communication between the endothelium and smooth muscle. In particular, a number of proteins localized to the MEJ mediate calcium signaling and there is localized calcium release from the endoplasmic reticulum via the inositol (1, 4, 5) trisphosphate receptor that can influence vascular tone and negative feedback. There is a detailed description of the creation and isolation of in vitro MEJ using the vascular cell co-culture technique, which has allowed for deeper exploration of signaling molecules and processes occurring at the MEJ. Smooth muscle cells and endothelial cells grow on opposite sides of a filter inset, and the MEJ form within the holes of the filter. This model can be used to immunofluorescently label proteins or the cellular fractions can be individually isolated to investigate protein expression and phosphorylation via western blotting. Using this unique model, we show the in vitro MEJ has a unique lipid composition that is rich in diacylglycerol and phosphatidylserine. This likely facilitates localization of signaling molecules such as protein kinase C and selective activation of endothelial nitric oxide synthase. Additionally, the multifunctional protein calreticulin is highly expressed at the MEJ of resistance arteries and endothelial deletion of calreticulin results in impaired MEJ calcium signaling, thus vasoconstriction to phenylephrine and blood pressure. Our data suggests that EC monolayer Calr could be iii functionally different than MEJ-localized Calr, which may be located outside the ER.Further work will need to be done in order to clarify and confirm MEJ Calr function and how it affects calcium signaling at the MEJ specifically in response to phenylephrine. In summary, the MEJ is an important signaling microdomain strategically located in the wall of resistance arteries to mediate heterocellular communication.

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Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

Cited by 98 publications

References 879 publications

Endothelial and Smooth Muscle Cell Interactions in the Pathobiology of Pulmonary Hypertension

Endothelial and Smooth Muscle Cell Interactions in the Pathobiology of Pulmonary Hypertension

Glucopsychosine increases cytosolic calcium to induce calpain-mediated apoptosis of acute myeloid leukemia cells

Signaling Microdomains within the Myoendothelial Junction

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