scholarly journals Piezo1 is a mechanosensor channel in CNS capillaries

2021 ◽  
Vol 154 (9) ◽  
Author(s):  
Osama F. Harraz ◽  
Nicholas R. Klug ◽  
Amanda Senatore ◽  
Masayo Koide ◽  
Mark T. Nelson
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Ex Vivo ◽  
Outer Wall ◽  
Channel Blockers ◽  
Control Mechanisms ◽  
Hemodynamic Forces ◽  
Capillary Endothelial Cells ◽  
Patch Clamp Electrophysiology ◽  
And Function

Cerebral blood flow (CBF) is exquisitely controlled to meet the ever-changing demands of active neurons in the brain. Brain capillaries are equipped with sensors of neurovascular coupling agents released from neurons/astrocytes onto the outer wall of a capillary. While capillaries can translate external signals into electrical and Ca2+ changes, control mechanisms from the lumen are less clear. The continuous flux of red blood cells and plasma through narrow-diameter capillaries imposes mechanical forces on the luminal (inner) capillary wall. Whether—and, if so, how—the ever-changing CBF could be mechanically sensed in capillaries is not known. Here, we propose and provide evidence that the mechanosensitive Piezo1 channels operate as mechanosensors in CNS capillaries to ultimately regulate CBF. Patch clamp electrophysiology confirmed the expression and function of Piezo1 channels in brain cortical and retinal capillary endothelial cells. Mechanical or pharmacological activation of Piezo1 channels evoked currents that were sensitive to Piezo1 channel blockers. Using genetically encoded Ca2+ indicator (Cdh5-GCaMP8) mice, we observed that Piezo1 channel activation triggered Ca2+ signals in endothelial cells. An ex vivo pressurized retina preparation was employed to further explore the mechanosensitivity of capillary Piezo1-mediated Ca2+ signals. Genetic and pharmacologic manipulation of Piezo1 in endothelial cells had significant impacts on CBF, reemphasizing the crucial role of mechanosensation in blood flow control. In conclusion, this study shows that Piezo1 channels act as mechanosensors in capillaries, and that these channels initiate crucial Ca2+ signals. We further show that Piezo1 modulates CBF, an observation of profound significance for the control of brain blood flow in health and in disorders where hemodynamic forces are disrupted, such as hypertension.

scholarly journals Electro-Metabolic Sensing Through Capillary ATP-Sensitive K+ Channels and Adenosine to Control Cerebral Blood Flow

2021 ◽  
Author(s):  
Maria Sancho ◽  
Nicholas R. Klug ◽  
Amreen Mughal ◽  
Thomas J. Heppner ◽  
David Hill-Eubanks ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Vascular Function ◽  
Brain Activity ◽  
List Type ◽  
Capillary Endothelial Cells ◽  
Metabolic Sensing ◽  
Cellular Components

SUMMARYThe dense network of capillaries composed of capillary endothelial cells (cECs) and pericytes lies in close proximity to all neurons, ideally positioning it to sense neuro/glial-derived compounds that regulate regional and global cerebral perfusion. The membrane potential (VM) of vascular cells serves as the essential output in this scenario, linking brain activity to vascular function. The ATP-sensitive K+ channel (KATP) is a key regulator of vascular VM in other beds, but whether brain capillaries possess functional KATP channels remains unknown. Here, we demonstrate that brain capillary ECs and pericytes express KATP channels that robustly control VM. We further show that the endogenous mediator adenosine acts through A2A receptors and the Gs/cAMP/PKA pathway to activate capillary KATP channels. Moreover, KATP channel stimulation in vivo causes vasodilation and increases cerebral blood flow (CBF). These findings establish the presence of KATP channels in cECs and pericytes and suggest their significant influence on CBF.HIGHLIGHTSCapillary network cellular components—endothelial cells and pericytes—possess functional KATP channels.Activation of KATP channels causes profound hyperpolarization of capillary cell membranes.Capillary KATP channels are activated by exogenous adenosine via A2A receptors and cAMP-dependent protein kinase.KATP channel activation by adenosine or synthetic openers increases cerebral blood flow.

Influence of subendocardial ischemia on transmural myocardial function

1992 ◽  
Vol 262 (2) ◽  
pp. H568-H576 ◽  
Author(s):  
N. C. Edwards ◽  
A. J. Sinusas ◽  
J. D. Bergin ◽  
D. D. Watson ◽  
M. Ruiz ◽  
...  
Keyword(s):  
Blood Flow ◽  
Myocardial Function ◽  
Outer Wall ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Left Ventricular ◽  
Actual Flow ◽  
Myocardial Thickening ◽  
And Function ◽  
The Relationship

The relationship between regional myocardial perfusion and function under ischemic conditions was examined by using a nontraumatic single-crystal pulsed Doppler system that permits complete transmural assessment of myocardial thickening. Sixteen open-chest dogs underwent either 50 (n = 4) or 180 (n = 12) min of partial coronary artery occlusion. Simultaneous measurements of myocardial thickening fraction (TF) and microsphere-determined blood flow (BF) were taken in the subepicardial, midwall, and subendocardial thirds of the left ventricular wall. During ischemia, there was an excellent correlation between BF and TF in the subendocardium. Mean subendocardial BF was reduced to 0.45 +/- 0.3 ml.min-1.g-1, resulting in a subendocardial TF of 0.8 +/- 19%. Although subepicardial BF was relatively preserved at 1.03 +/- 0.4 ml.min-1.g-1, subepicardial TF was diminished markedly and not significantly different from subendocardial TF. Subepicardial and midwall TF were highly dependent on subendocardial flow rather than on the actual flow in these areas. Hence these studies show a marked dependence of transmural myocardial function on subendocardial blood flow. Outer wall function is more dependent on subendocardial than subepicardial blood flow.

Ontogeny of Hematopoiesis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. SCI-4-SCI-4
Author(s):  
Elaine Dzierzak
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Transcription Factors ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Developmental Time ◽  
Hematopoietic Cell ◽  
Conditional Knockout ◽  
Hematopoietic Stem ◽  
And Function

Abstract The current challenge in hematopoietic transplantation and regeneration therapies is acquiring and/or producing a reliable and plentiful source of hematopoietic stem cells (HSCs). Given that HSCs from bone marrow, peripheral, or umbilical cord blood undergo only limited/no expansion ex vivo, there is a high interest in understanding how the adult cohort of multipotent self-renewing HSCs are generated and expanded during embryonic development. The development of HSCs in vertebrate embryos begins in the major vasculature. HSCs are generated in a short window of developmental time starting at embryonic day E10.5 until E12 in the mouse embryo, and from gestational weeks four to six in the human embryo. The first HSCs, which are as potent as bone marrow HSCs in transplantation procedures, are generated in the aorta-gonad-mesonephros (AGM) region. HSCs are found in the major vasculature – aorta, vitelline artery, and umbilical artery – subsequent to the appearance of hematopoietic cell clusters closely associated with the lumenal walls of these vessels. The relationship of HSCs to these clusters and the identification of the precursors to HSCs have been recently established through genetic, phenotypic, and real-time imaging studies. Remarkably, HSCs and hematopoietic progenitors arise directly from a subset of endothelial cells (hemogenic endothelial cells) in a natural transdifferentiation event. They are made through a process called endothelial to hematopoietic cell transition (EHT). EHT and HSC generation is in part regulated through ventral-derived developmental signals and a group of pivotal (core) transcription factors, including Runx1 and Gata2. Conditional knockout strategies show that these transcription factors are required for the generation of vascular hematopoietic clusters and HSCs, suggesting a role in hematopoietic fate induction and/or cell expansion. Interestingly, whereas both Runx1 and Gata2 are required for HSC generation, only Gata2 remains essential in HSCs after their production. We are profiling hemogenic endothelial and HSCs by RNA sequencing so as to understand the complete genetic program that leads to generation of HSCs. These results will be discussed in the context of developmental signaling pathways (BMP4, Hedgehog, etc.) that appear to impact HSC generation and expansion, and the localized dynamic expression and function of Gata2 and Runx1 in vascular endothelial and hematopoietic cluster cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Flow-mediated endothelial mechanotransduction

1995 ◽  
Vol 75 (3) ◽  
pp. 519-560 ◽  
Author(s):  
P. F. Davies
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Blood Vessel ◽  
Vascular Tone ◽  
Shear Stresses ◽  
Mechanical Forces ◽  
Hemodynamic Forces ◽  
Atherosclerotic Lesions ◽  
Arterial Structure ◽  
Gene Regulatory

Mechanical forces associated with blood flow play important roles in the acute control of vascular tone, the regulation of arterial structure and remodeling, and the localization of atherosclerotic lesions. Major regulation of the blood vessel responses occurs by the action of hemodynamic shear stresses on the endothelium. The transmission of hemodynamic forces throughout the endothelium and the mechanotransduction mechanisms that lead to biophysical, biochemical, and gene regulatory responses of endothelial cells to hemodynamic shear stresses are reviewed.

scholarly journals A blood flow–dependent klf2a-NO signaling cascade is required for stabilization of hematopoietic stem cell programming in zebrafish embryos

Blood ◽  
2011 ◽  
Vol 118 (15) ◽  
pp. 4102-4110 ◽  
Author(s):  
Lu Wang ◽  
Panpan Zhang ◽  
Yonglong Wei ◽  
Ya Gao ◽  
Roger Patient ◽  
...  
Keyword(s):  
Blood Flow ◽  
Signaling Cascade ◽  
Zebrafish Embryos ◽  
Hematopoietic Stem ◽  
Hemodynamic Forces ◽  
No Signaling ◽  
Vessel Development ◽  
And Function ◽  
Chip Analysis

Abstract Blood flow has long been thought to be important for vessel development and function, but its role in HSC development is not yet fully understood. Here, we take advantage of zebrafish embryos with circulation defects that retain relatively normal early development to illustrate the combinatorial roles of genetic and hemodynamic forces in HSC development. We show that blood flow is not required for initiation of HSC gene expression, but instead is indispensable for its maintenance. Knockdown of klf2a mimics the silent heart (sih/tnnt2a) phenotype while overexpression of klf2a in tnnt2a morphant embryos can rescue HSC defects, suggesting that klf2a is a downstream mediator of blood flow. Furthermore, the expression of NO synthase (nos) was reduced in klf2a knockdown embryos, and ChIP analysis showed that endogenous Klf2a is bound to the promoters of nos genes in vivo, indicating direct gene regulation. Finally, administration of the NO agonist S-nitroso N-acetylpenicillamine (SNAP) can restore HSC development in tnnt2a and klf2a morphants, suggesting that NO signaling is downstream of Klf2a which is induced by hemodynamic forces. Taken together, we have demonstrated that blood flow is essential for HSC development and is mediated by a klf2a-NO signaling cascade in zebrafish.

scholarly journals Neural activity drives dynamic Ca2+ signals in capillary endothelial cells that shape local brain blood flow

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Thomas Longden ◽  
Osama Harraz ◽  
Grant Hennig ◽  
Bo Shui ◽  
Frank Lee ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Neural Activity ◽  
Brain Blood Flow ◽  
Capillary Endothelial Cells ◽  
Local Brain

scholarly journals Hypergravity Activates a Pro-Angiogenic Homeostatic Response by Human Capillary Endothelial Cells

2020 ◽  
Vol 21 (7) ◽  
pp. 2354 ◽  
Author(s):  
Chiara De Cesari ◽  
Ivana Barravecchia ◽  
Olga V. Pyankova ◽  
Matteo Vezza ◽  
Marco M. Germani ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Bed Rest ◽  
Tube Formation ◽  
Negative Effects ◽  
Sensitive Organ ◽  
Capillary Endothelial Cells ◽  
And Function ◽  
Disease Exposure ◽  
Dose Dependent Increase ◽  
Homeostatic Response

Capillary endothelial cells are responsible for homeostatic responses to organismic and environmental stimulations. When malfunctioning, they may cause disease. Exposure to microgravity is known to have negative effects on astronauts’ physiology, the endothelium being a particularly sensitive organ. Microgravity-related dysfunctions are striking similar to the consequences of sedentary life, bed rest, and ageing on Earth. Among different countermeasures implemented to minimize the effects of microgravity, a promising one is artificial gravity. We examined the effects of hypergravity on human microvascular endothelial cells of dermal capillary origin (HMEC-1) treated at 4 g for 15 min, and at 20 g for 15 min, 3 and 6 h. We evaluated cell morphology, gene expression and 2D motility and function. We found a profound rearrangement of the cytoskeleton network, dose-dependent increase of Focal Adhesion kinase (FAK) phosphorylation and Yes-associated protein 1 (YAP1) expression, suggesting cell stiffening and increased proneness to motility. Transcriptome analysis showed expression changes of genes associated with cardiovascular homeostasis, nitric oxide production, angiogenesis, and inflammation. Hypergravity-treated cells also showed significantly improved motility and function (2D migration and tube formation). These results, expanding our knowledge about the homeostatic response of capillary endothelial cells, show that adaptation to hypergravity has opposite effect compared to microgravity on the same cell type.

Sign in / Sign up

Export Citation Format

Share Document