Intracellular recording and dye transfer in arterioles during blood flow control

Segal, Steven S.; Bény, Jean‐Louis

doi:10.1152/ajpheart.1992.263.1.h1

Cited by 92 publications

(116 citation statements)

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“…1C) was <10 mV more negative than the vascular voltages measured at experimentally advantageous in vivo sites, such as the rat cremaster muscle (−42 mV) and the hamster cheek pouch (−46 mV) (27,28). Thus, a lack of internal pressurization does not account for the suprahyperpolarized membrane potentials of ∼-90 mV that we recorded in arterioles of nonperfused ex vivo <P30 ROP retinas (Fig.…”

Section: Discussionmentioning

confidence: 62%

Bioelectric impact of pathological angiogenesis on vascular function

Puro

Kohmoto

Fujita

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Pathological angiogenesis, as seen in many inflammatory, immune, malignant, and ischemic disorders, remains an immense health burden despite new molecular therapies. It is likely that further therapeutic progress requires a better understanding of neovascular pathophysiology. Surprisingly, even though transmembrane voltage is well known to regulate vascular function, no previous bioelectric analysis of pathological angiogenesis has been reported. Using the perforated-patch technique to measure vascular voltages in human retinal neovascular specimens and rodent models of retinal neovascularization, we discovered that pathological neovessels generate extraordinarily high voltage. Electrophysiological experiments demonstrated that voltage from aberrantly located preretinal neovascular complexes is transmitted into the intraretinal vascular network. With extensive neovascularization, this voltage input is substantial and boosts the membrane potential of intraretinal blood vessels to a suprahyperpolarized level. Coincident with this suprahyperpolarization, the vasomotor response to hypoxia is fundamentally altered. Instead of the compensatory dilation observed in the normal retina, arterioles constrict in response to an oxygen deficiency. This anomalous vasoconstriction, which would potentiate hypoxia, raises the possibility that the bioelectric impact of neovascularization on vascular function is a previously unappreciated pathophysiological mechanism to sustain hypoxia-driven angiogenesis.neovascularization | proliferative retinopathy | retinopathy of prematurity | proliferative diabetic retinopathy | retina T he abnormal growth of blood vessels is a key pathophysiological feature of numerous disorders, including tumorigenesis, arthritis, endometriosis, and retinopathies. Despite substantial progress from studies of patients and animal models, abnormal neovascularization remains a common threat to health and wellbeing. To help address this challenge, we devised a unique experimental approach to better understand neovascular pathophysiology. Because almost nothing is known about the electrogenic profile of neovascular complexes and how these complexes functionally interact with their parent vessels, we focused on the bioelectric features of neovascularization. These gaps in knowledge are surprising, considering that it is well established that the transmembrane voltage of vascular cells (1), as well as electrotonic cell-cell interactions within a vascular network (2-4), play vital roles in regulating blood flow.In this electrophysiological analysis of pathological angiogenesis, we focused on abnormal vasoproliferation in rodent and human retinas. For multiple reasons, the retina is an ideal tissue for this undertaking. First is its clinical importance. Retinal vasoproliferation is the major cause of blindness in prematurely born infants (retinopathy of prematurity) and persons with diabetes (proliferative diabetic retinopathy) and sickle cell disease (sickle cell retinopathy). The hallmark of these disorders is abno...

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Section: Discussionmentioning

confidence: 62%

Bioelectric impact of pathological angiogenesis on vascular function

Puro

Kohmoto

Fujita

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Evidence supporting the role of gap junctions includes the observation that conducted vasomotor responses in hamster cheek pouch are abolished or attenuated with the application of putative gap junction uncouplers (35,43). Moreover, electron microscopy has demonstrated that neighboring endothelial and smooth muscle cells in renal vasculature (29), thoracic aorta (36), and iridial arterioles (18) are connected by gap junctions, which render these cells electrically and chemically coupled (2,3,18,40,34,23,28,42,43). See Ref.…”

Section: Discussionmentioning

confidence: 99%

Autoregulation and conduction of vasomotor responses in a mathematical model of the rat afferent arteriole

Sgouralis

Layton

2012

American Journal of Physiology-Renal Physiology

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Steinhausen et al. (37) analyzed the propagation of vasomotor responses, induced by local electrical stimulation, in split hydronephrotic rat kidneys. Their results indicate that the responses decay with increasing distance from the stimulation site and that the decay is significantly faster upstream than downstream. An explanation for the asymmetric decay rates, which was elusive, is a motivation for the present study.In a previous study (5), we developed a detailed mathematical model of the myogenic response of a small segment of the afferent arteriole (AA) wall, including the endothelium and the surrounding smooth muscle cells. That model was used to examine the response of the AA segment to changes in mean and pulsatile pressure. Simulation results of that model are consistent with the hypothesis that the AA myogenic response plays an important role in protecting the glomerular capillaries against elevated systolic pressures. The goal of this study is to develop a multicell model of the AA by connecting a series of AA smooth muscle cells and endothelial cells via gap junction coupling and to use the model to study the myogenic response of the AA and its response to local electrical stimulation. The AA model is intended to be used as an essential component in models of integrated renal hemodynamic regulation. MATHEMATICAL MODELMulticell AA model. The model is an extension of our previous AA cell model (5) and represents a segment of an AA of length L (L ϳ300 m), consisting of a series of N cell ϭ 101 smooth muscle cell models (5), coupled via their gap junctions and via an endothelial cell layer. (An odd number of smooth muscle cell models were represented so that there is a middle cell that can be stimulated to study any asymmetry in the conduction of vasoconstrictive response.) The model AA segment is connected in series to a fixed resistor, denoted R end. The inflow pressure [P 0(t) at x ϭ 0] and the pressure at the end of the fixed resistor P end (at x ϭ 2L) are assumed to be known a priori. A schematic diagram is shown in Fig. 1. When the inflow pressure P 0 is varied or when a vasoconstrictive or vasodilative response is induced, the pressure at the end of the AA segment, which is denoted P(L, t) and which we refer to as the "outflow pressure," may also vary. We set P end to 0 mmHg and R end to equal the time-averaged value of the total resistance of the unstimulated AA with P 0 ϭ 100 mmHg, so that when the inflow pressure P 0 ϭ 100 mmHg, the outflow pressure P(L) Ϸ 50 mmHg.Each AA smooth muscle cell model incorporates the ionic transports, cell membrane potential, muscle contraction of the AA smooth muscle cells, and the mechanics of a thick-walled cylinder. The model represents the interaction of Ca 2ϩ and K ϩ fluxes mediated by voltagegated and voltage-calcium-gated channels, respectively, which gives rise to the periodicity of those transports. This results in a timeperiodic cytoplasmic calcium concentration, myosin light chains phosphorylation, and crossbridge formation with the attending muscle s...

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“…Because there is evidence that cAMP can enhance the molecular permeability and electrical conductance of gap junctions (14-18), we therefore investigated its ability to modulate dye transfer in the vessel wall. Attempts to demonstrate communication via myoendothelial gap junctions by injecting tracer dyes into individual endothelial cells are usually unsuccessful (25)(26)(27), presumably because of preferential diffusion of dye between cells in the endothelial monolayer, which are highly coupled by large gap junction plaques (19,28). To overcome this ''sink-source'' problem, we therefore selectively loaded the entire endothelium of femoral artery segments by intraluminal perfusion with the cell permeant dye calcein AM (29), so that fluorescence could be assessed in the media by confocal microscopy after hydrolysis to calcein.…”

Section: Discussionmentioning

confidence: 99%

cAMP facilitates EDHF-type relaxations in conduit arteries by enhancing electrotonic conduction via gap junctions

Griffith

Chaytor

Taylor

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

106

109

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We have investigated the role of cAMP in NO-and prostanoidindependent relaxations that are widely attributed to an endothelium-derived hyperpolarizing factor (EDHF). Under control conditions EDHF-type relaxations evoked by acetylcholine (ACh) in rabbit iliac arteries were transient, but in the presence of the cAMP phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) or the cell permeant cAMP analog 8-bromo-cAMP, relaxations became sustained with their maxima potentiated Ϸ2-fold. Relaxation was associated with transient Ϸ1.5-fold elevations in smooth muscle cAMP levels with both mechanical and nucleotide responses being abolished by interrupting gap junctional communication with the connexin-mimetic peptide Gap 27 and by endothelial denudation. However, IBMX induced a sustained endothelium-independent Ϸ2-fold rise in cAMP levels, which was not further amplified by ACh, suggesting that the contribution of cAMP to the EDHF phenomenon is permissive. After selective loading of the endothelium with calcein AM, direct transfer of dye from the endothelium to the media was enhanced by IBMX or 8-bromo-cAMP, but not by 8-bromo-cGMP, whereas Gap 27 promoted sequestration within the intima. ACh-induced hyperpolarizations of subintimal smooth muscle in arterial strips with intact endothelium were abolished by Gap 27 and the adenylyl cyclase inhibitor 2 ,5 -dideoxyadenosine but were unaffected by IBMX. By contrast, in strips partially denuded of endothelium, IBMX enhanced the transmission of hyperpolarization from the endothelium to remote smooth muscle cells. These findings support the hypothesis that endothelial hyperpolarization underpins the EDHF phenomenon, with cAMP governing subsequent electrotonic signaling via both myoendothelial and homocellular smooth muscle gap junctions.connexin ͉ acetylcholine ͉ IBMX ͉ 8-bromo-cAMP ͉ cGMP

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Intracellular recording and dye transfer in arterioles during blood flow control

Cited by 92 publications

References 0 publications

Bioelectric impact of pathological angiogenesis on vascular function

Bioelectric impact of pathological angiogenesis on vascular function

Autoregulation and conduction of vasomotor responses in a mathematical model of the rat afferent arteriole

cAMP facilitates EDHF-type relaxations in conduit arteries by enhancing electrotonic conduction via gap junctions

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