The microcirculation is responsible for orchestrating adjustments in vascular tone to match local tissue perfusion with oxygen demand. Beyond this metabolic dilation, the microvasculature plays a ...critical role in modulating vascular tone by endothelial release of an unusually diverse family of compounds including nitric oxide, other reactive oxygen species, and arachidonic acid metabolites. Animal models have provided excellent insight into mechanisms of vasoregulation in health and disease. However, there are unique aspects of the human microcirculation that serve as the focus of this review. The concept is put forth that vasculoparenchymal communication is multimodal, with vascular release of nitric oxide eliciting dilation and preserving normal parenchymal function by inhibiting inflammation and proliferation. Likewise, in disease or stress, endothelial release of reactive oxygen species mediates both dilation and parenchymal inflammation leading to cellular dysfunction, thrombosis, and fibrosis. Some pathways responsible for this stress-induced shift in mediator of vasodilation are proposed. This paradigm may help explain why microvascular dysfunction is such a powerful predictor of cardiovascular events and help identify new approaches to treatment and prevention.
Mitochondrial dysfunction results in high levels of oxidative stress and mitochondrial damage, leading to disruption of endothelial homeostasis. Recent discoveries have clarified several pathways, ...whereby mitochondrial dysregulation contributes to endothelial dysfunction and vascular disease burden. One such pathway centers around peroxisome proliferator receptor-γ coactivator 1α (PGC-1α), a transcriptional coactivator linked to mitochondrial biogenesis and antioxidant defense, among other functions. Although primarily investigated for its therapeutic potential in obesity and skeletal muscle differentiation, the ability of PGC-1α to alter a multitude of cellular functions has sparked interest in its role in the vasculature. Within this context, recent studies demonstrate that PGC-1α plays a key role in endothelial cell and smooth muscle cell regulation through effects on oxidative stress, apoptosis, inflammation, and cell proliferation. The ability of PGC-1α to affect these parameters is relevant to vascular disease progression, particularly in relation to atherosclerosis. Upregulation of PGC-1α can prevent the development of, and even encourage regression of, atherosclerotic lesions. Therefore, PGC-1α is poised to serve as a promising target in vascular disease. This review details recent findings related to PGC-1α in vascular regulation, regulation of PGC-1α itself, the role of PGC-1α in atherosclerosis, and therapies that target this key protein.
Coronary artery disease (CAD) is associated with a compensatory switch in mechanism of flow-mediated dilation (FMD) from nitric oxide (NO) to H
O
. The underlying mechanism responsible for the ...pathological shift is not well understood, and recent reports directly implicate telomerase and indirectly support a role for autophagy. We hypothesize that autophagy is critical for shear stress-induced release of NO and is a crucial component of for the pathway by which telomerase regulates FMD. Approach and Results: Human left ventricular, atrial, and adipose resistance arterioles were collected for videomicroscopy and immunoblotting. FMD and autophagic flux were measured in arterioles treated with autophagy modulators alone, and in tandem with telomerase-activity modulators. LC3B II/I was higher in left ventricular tissue from patients with CAD compared with non-CAD (2.8±0.2 versus 1.0±0.2-fold change;
<0.05), although p62 was similar between groups. Shear stress increased Lysotracker fluorescence in non-CAD arterioles, with no effect in CAD arterioles. Inhibition of autophagy in non-CAD arterioles induced a switch from NO to H
O
, while activation of autophagy restored NO-mediated vasodilation in CAD arterioles. In the presence of an autophagy activator, telomerase inhibitor prevented the expected switch (Control: 82±4%; NG-Nitro-l-arginine methyl ester: 36±5%; polyethylene glycol catalase: 80±3). Telomerase activation was unable to restore NO-mediated FMD in the presence of autophagy inhibition in CAD arterioles (control: 72±7%; NG-Nitro-l-arginine methyl ester: 79±7%; polyethylene glycol catalase: 38±9%).
We provide novel evidence that autophagy is responsible for the pathological switch in dilator mechanism in CAD arterioles, demonstrating that autophagy acts downstream of telomerase as a common denominator in determining the mechanism of FMD.
Microvascular dysfunction predicts adverse cardiovascular events despite absence of large vessel disease. A shift in the mediator of flow‐mediated dilatation (FMD) from nitric oxide (NO) to ...mitochondrial‐derived hydrogen peroxide (H2O2) occurs in arterioles from patients with coronary artery disease (CAD). The underlying mechanisms governing this shift are not completely defined. Lipid phosphate phosphatase 3 (LPP3) is a transmembrane protein that dephosphorylates lysophosphatidic acid, a bioactive lipid, causing a receptor‐mediated increase in reactive oxygen species. A single nucleotide loss‐of‐function polymorphism in the gene coding for LPP3 (rs17114036) is associated with elevated risk for CAD, independent of traditional risk factors. LPP3 is suppressed by miR‐92a, which is elevated in the circulation of patients with CAD. Repression of LPP3 increases vascular inflammation and atherosclerosis in animal models. We investigated the role of LPP3 and miR‐92a as a mechanism for microvascular dysfunction in CAD. We hypothesized that modulation of LPP3 is critically involved in the disease‐associated shift in mediator of FMD. LPP3 protein expression was reduced in left ventricle tissue from CAD relative to non‐CAD patients (P = 0.004), with mRNA expression unchanged (P = 0.96). Reducing LPP3 expression (non‐CAD) caused a shift from NO to H2O2 (% maximal dilatation: Control 78.1 ± 11.4% vs. Peg‐Cat 30.0 ± 11.2%; P < 0.0001). miR‐92a is elevated in CAD arterioles (fold change: 1.9 ± 0.01 P = 0.04), while inhibition of miR‐92a restored NO‐mediated FMD (CAD), and enhancing miR‐92a expression (non‐CAD) elicited H2O2‐mediated dilatation (P < 0.0001). Our data suggests LPP3 is crucial in the disease‐associated switch in the mediator of FMD.
Key points
Lipid phosphate phosphatase 3 (LPP3) expression is reduced in heart tissue patients with coronary artery disease (CAD).
Loss of LPP3 in CAD is associated with an increase in the LPP3 inhibitor, miR‐92a.
Inhibition of LPP3 in the microvasculature of healthy patients mimics the CAD flow‐mediated dilatation (FMD) phenotype.
Inhibition of miR‐92a restores nitric oxide‐mediated FMD in the microvasculature of CAD patients.
figure legend Maintenance of lipid phosphate phosphatase 3 (LPP3) maintains microvascular function in health and disease. In healthy microvasculature, LPP3 helps transduce the production of shear‐induced nitric oxide (NO) formation to induce smooth muscle relaxation (flow‐mediated dilatation). In microvascular disease, such as coronary artery disease, miR‐92a inhibits expression of LPP3, and increases production of mitochondrial‐derived reactive oxygen species (ROS) to cause a switch in the mechanism of microvascular flow‐mediated dilatation from NO to H2O2.
Crossing signals: bioactive lipids in the microvasculature Chabowski, Dawid S; Cohen, Katie E; Abu-Hatoum, Ossama ...
American journal of physiology. Heart and circulatory physiology,
05/2020, Letnik:
318, Številka:
5
Journal Article
Recenzirano
Odprti dostop
The primary function of the arterial microvasculature is to ensure that regional perfusion of blood flow is matched to the needs of the tissue bed. This critical physiological mechanism is tightly ...controlled and regulated by a variety of vasoactive compounds that are generated and released from the vascular endothelium. Although these substances are required for modulating vascular tone, they also influence the surrounding tissue and have an overall effect on vascular, as well as parenchymal, homeostasis. Bioactive lipids, fatty acid derivatives that exert their effects through signaling pathways, are included in the list of vasoactive compounds that modulate the microvasculature. Although lipids were identified as important vascular messengers over three decades ago, their specific role within the microvascular system is not well defined. Thorough understanding of these pathways and their regulation is not only essential to gain insight into their role in cardiovascular disease but is also important for preventing vascular dysfunction following cancer treatment, a rapidly growing problem in medical oncology. The purpose of this review is to discuss how biologically active lipids, specifically prostanoids, epoxyeicosatrienoic acids, sphingolipids, and lysophospholipids, contribute to vascular function and signaling within the endothelium. Methods for quantifying lipids will be briefly discussed, followed by an overview of the various lipid families. The cross talk in signaling between classes of lipids will be discussed in the context of vascular disease. Finally, the potential clinical implications of these lipid families will be highlighted.
Blood flow through healthy human vessels releases NO to produce vasodilation, whereas in patients with coronary artery disease (CAD), the mediator of dilation transitions to mitochondria-derived ...hydrogen peroxide (
H
O
). Excessive
H
O
production contributes to a proatherosclerotic vascular milieu. Loss of PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α) is implicated in the pathogenesis of CAD. We hypothesized that PGC-1α suppresses
H
O
production to reestablish NO-mediated dilation in isolated vessels from patients with CAD. Isolated human adipose arterioles were cannulated, and changes in lumen diameter in response to graded increases in flow were recorded in the presence of PEG (polyethylene glycol)-catalase (H
O
scavenger) or L-NAME (
-nitro-l-arginine methyl ester; NOS inhibitor). In contrast to the exclusively NO- or H
O
-mediated dilation seen in either non-CAD or CAD conditions, respectively, flow-mediated dilation in CAD vessels was sensitive to both L-NAME and PEG-catalase after PGC-1α upregulation using ZLN005 and α-lipoic acid. PGC-1α overexpression in CAD vessels protected against the vascular dysfunction induced by an acute increase in intraluminal pressure. In contrast, downregulation of PGC-1α in non-CAD vessels produces a CAD-like phenotype characterized by
H
O
-mediated dilation (no contribution of NO). Loss of PGC-1α may contribute to the shift toward the
H
O
-mediated dilation observed in vessels from subjects with CAD. Strategies to boost PGC-1α levels may provide a therapeutic option in patients with CAD by shifting away from
H
O
-mediated dilation, increasing NO bioavailability, and reducing levels of
H
O
Furthermore, increased expression of PGC-1α allows for simultaneous contributions of both NO and H
O
to flow-mediated dilation.
Background and Purpose
NO produces arteriolar flow‐induced dilation (FID) in healthy subjects but is replaced by mitochondria‐derived hydrogen peroxide (mtH2O2) in patients with coronary artery ...disease (CAD). Lysophosphatidic acid (LPA) is elevated in patients with risk factors for CAD, but its functional effect in arterioles is unknown. We tested whether elevated LPA changes the mediator of FID from NO to mtH2O2 in human visceral and subcutaneous adipose arterioles.
Experimental Approach
Arterioles were cannulated on glass micropipettes and pressurized to 60 mmHg. We recorded lumen diameter after graded increases in flow in the presence of either NOS inhibition (L‐NAME) or H2O2 scavenging (Peg‐Cat) ± LPA (10 μM, 30 min), ±LPA1/LPA3 receptor antagonist (Ki16425) or LPA2 receptor antagonist (H2L5186303). We analysed LPA receptor RNA and protein levels in human arterioles and human cultured endothelial cells.
Key Results
FID was inhibited by L‐NAME but not Peg‐Cat in untreated vessels. In vessels treated with LPA, FID was of similar magnitude but inhibited by Peg‐Cat while L‐NAME had no effect. Rotenone attenuated FID in vessels treated with LPA indicating mitochondria as a source of ROS. RNA transcripts from LPA1 and LPA2 but not LPA3 receptors were detected in arterioles. LPA1 but not LPA3 receptor protein was detected by Western blot. Pretreatment of vessels with an LPA1/LPA3, but not LPA2, receptor antagonist prior to LPA preserved NO‐mediated dilation.
Conclusions and Implications
These findings suggest an LPA1 receptor‐dependent pathway by which LPA increases arteriolar release of mtH2O2 as a mediator of FMD.
Objectives
KV channels are important regulators of vascular tone, but the identity of specific KV channels involved and their regulation in disease remain less well understood. We determined the ...expression of KV1 channel subunits and their role in cAMP‐mediated dilation in coronary resistance arteries from subjects with and without CAD.
Methods
HCAs from patients with and without CAD were assessed for mRNA and protein expression of KV1 channel subunits with molecular techniques and for vasodilator response with isolated arterial myography.
Results
Assays of mRNA transcripts, membrane protein expression, and vascular cell‐specific localization revealed abundant expression of KV1.5 in vascular smooth muscle cells of non‐CAD HCAs. Isoproterenol and forskolin, two distinct cAMP‐mediated vasodilators, induced potent dilation of non‐CAD arterioles, which was inhibited by both the general KV blocker 4‐AP and the selective KV1.5 blocker DPO‐1. The cAMP‐mediated dilation was reduced in CAD and was accompanied by a loss of or reduced contribution of 4‐AP‐sensitive KV channels.
Conclusions
KV1.5, as a major 4‐AP‐sensitive KV1 channel expressed in coronary VSMCs, mediates cAMP‐mediated dilation in non‐CAD arterioles. The cAMP‐mediated dilation is reduced in CAD coronary arterioles, which is associated with impaired 4‐AP‐sensitive KV channel function.
Hydrogen peroxide (H
O
) regulates vascular tone in the human microcirculation under physiological and pathophysiological conditions. It dilates arterioles by activating large-conductance Ca
...-activated K
channels in subjects with coronary artery disease (CAD), but its mechanisms of action in subjects without CAD (non-CAD) when compared with those with CAD remain unknown.
We hypothesize that H
O
-elicited dilation involves different K
channels in non-CAD versus CAD, resulting in an altered capacity for vasodilation during disease.
H
O
induced endothelium-independent vasodilation in non-CAD adipose arterioles, which was reduced by paxilline, a large-conductance Ca
-activated K
channel blocker, and by 4-aminopyridine, a voltage-gated K
(K
) channel blocker. Assays of mRNA transcripts, protein expression, and subcellular localization revealed that K
1.5 is the major K
1 channel expressed in vascular smooth muscle cells and is abundantly localized on the plasma membrane. The selective K
1.5 blocker diphenylphosphine oxide-1 and the K
1.3/1.5 blocker 5-(4-phenylbutoxy)psoralen reduced H
O
-elicited dilation to a similar extent as 4-aminopyridine, but the selective K
1.3 blocker phenoxyalkoxypsoralen-1 was without effect. In arterioles from CAD subjects, H
O
-induced dilation was significantly reduced, and this dilation was inhibited by paxilline but not by 4-aminopyridine, diphenylphosphine oxide-1, or 5-(4-phenylbutoxy)psoralen. K
1.5 cell membrane localization and diphenylphosphine oxide-1-sensitive K
currents were markedly reduced in isolated vascular smooth muscle cells from CAD arterioles, although mRNA or total cellular protein expression was largely unchanged.
In human arterioles, H
O
-induced dilation is impaired in CAD, which is associated with a transition from a combined large-conductance Ca
-activated K
- and K
(K
1.5)-mediated vasodilation toward a large-conductance Ca
-activated K
-predominant mechanism of dilation. Loss of K
1.5 vasomotor function may play an important role in microvascular dysfunction in CAD or other vascular diseases.
Introduction
Flow‐induced dilation (FID) in arterioles from patients with coronary artery disease (CAD) is dependent on hydrogen peroxide (H2O2) rather than the nitric oxide (NO)‐mediated mechanism ...observed in arterioles from patients without CAD. Circulating levels of lysophosphatidic acid (LPA), a bioactive lipid, range from low to high nanomolar levels in healthy individuals, but increase to micromolar levels in patients with risk factors for CAD as well as early and advanced stages of atherosclerosis. Studies from our laboratory show that acute (30 min) exposure to 10μM LPA in vessels from patients without CAD shifts the mediator of FID from NO to H2O2, recapitulating the CAD phenotype. LPA effects are mediated through cognate LPA receptors, but it is unknown which receptors are expressed in human arterioles and may be responsible for the observed LPA‐induced shift in the mediator of FID. Based on our observed expression pattern of LPA receptors in human arterioles, we hypothesized that LPA‐induced switch to H2O2 as the mediator of FID is mediated by LPA1 receptor, and the shift can be prevented by blocking the receptor prior to LPA challenge.
Methods
Human arterioles from discarded adipose tissue were isolated and prepared for videomicroscopy. Arterioles from subjects without CAD were treated with LPA (10uM, 30 min) +Ki16425 (LPA1/3 receptor antagonist, 10μM, 30 min) or LPA+H2L5186303 (LPA2 receptor antagonist, 1μM, 30 min). Diameters were measured at steady‐state during graded increases in intraluminal pressure gradients (flow) in the presence/absence of a NOS inhibitor (L‐NAME; 100μM) or H2O2 scavenger (Peg‐Catalase; 500 units/mL). Data are expressed as % maximal dilation. RT‐qPCR was performed on intact vessels from CAD and non‐CAD patients to examine LPA1–3 receptor target sequences. Values were normalized to 18s.
Results
mRNA levels of LPA1 and LPA2 receptors were expressed at the same level in vessels from CAD and non‐CAD patients. There was no detection of LPA3 receptor in either CAD or non‐CAD arterioles. Blocking LPA1/3 receptors prevented the switch to H2O2‐dependent FID from occurring (LPA+Ki16425 control: 81.9±4.1 vs Ki16425+LPA+L‐NAME: *23.8±8.7 vs Ki16425+LPA+Peg‐Cat: 79.1±4.4, n=8,7,7). Blocking LPA2 receptor did not alter the LPA‐induced shift to H2O2‐mediated FID (LPA+H2L5186303 control: 83.0±4.2 vs (LPA+H2L5186303+L‐NAME 84.2±3.0 vs (LPA+H2L5186303+Peg‐Cat *−9.72±2.0, n=6,6,6). *p<0.05, 2‐way ANOVA.
Conclusion
Blockade of LPA1/3 receptors before exposing the vessels to pathophysiological levels of LPA preserved NO‐mediated dilation in non‐CAD arterioles, whereas blocking LPA2 receptors did not protect LPA‐exposed vessels from shifting to H2O2 as the mediator of FID. Functional data and the expression pattern of the three receptors suggest that the LPA effect is mediated by activation of LPA1 receptor. Blocking LPA1 receptor may be an effective strategy to preserve NO‐mediated FID in the arterioles of patients with elevated levels of LPA.
Support or Funding Information
This work was supported by the AHA Predoctoral Fellowship ‐ Midwest Affiliate 17PRE33410986 (to D.S. Chabowski) and the National Institutes of Health RO1 HL135901‐01 (to D.D. Gutterman).
This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.
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