Loss of Collectrin, an Angiotensin-Converting Enzyme 2 Homolog, Uncouples Endothelial Nitric Oxide Synthase and Causes Hypertension and Vascular Dysfunction

Cechova, Sylvia; Zeng, Qing; Billaud, Marie; Mutchler, Stephanie; Rudy, Christine K.; Straub, Adam C.; Chi, Liqun; Chan, Florence; Hu, Jun; Griffiths, Robert; Howell, Nancy L; Madsen, Kirsten; Jensen, Boye L.; Palmer, Lisa A.; Carey, Robert M.; Sung, Sun-sang J.; Malakauskas, Sandra M.; Isakson, Brant E.; Le, Thu H.

doi:10.1161/circulationaha.113.003301

Cited by 38 publications

(49 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The catheter of a radiotelemetry unit (TA11PA-C10, DSI) was implanted in the mouse left carotid artery under isoflurane anesthesia, and the catheter was tunneled trough the radio-transmitter placed in a subcutaneous pouch along the right flank of the mouse, as previously described (74). After implantation, mice were allowed to recover for 7 days.…”

Section: Methodsmentioning

confidence: 99%

A molecular signature in the pannexin1 intracellular loop confers channel activation by the α1 adrenoreceptor in smooth muscle cells

et al. 2015

Self Cite

View full text Add to dashboard Cite

Both purinergic signaling through nucleotides such as ATP (adenosine 5′-triphosphate) and noradrenergic signaling through molecules such as norepinephrine regulate vascular tone and blood pressure. Pannexin1 (Panx1), which forms large-pore, ATP-releasing channels, is present in vascular smooth muscle cells in peripheral blood vessels and participates in noradrenergic responses. Using pharmacological approaches and mice conditionally lacking Panx1 in smooth muscle cells, we found that Panx1 contributed to vaso-constriction mediated by the α1 adrenoreceptor (α1AR), whereas vasoconstriction in response to serotonin or endothelin-1 was independent of Panx1. Analysis of the Panx1-deficient mice showed that Panx1 contributed to blood pressure regulation especially during the night cycle when sympathetic nervous activity is highest. Using mimetic peptides and site-directed mutagenesis, we identified a specific amino acid sequence in the Panx1 intracellular loop that is essential for activation by α1AR signaling. Collectively, these data describe a specific link between noradrenergic and purinergic signaling in blood pressure homeostasis.

show abstract

Section: Methodsmentioning

confidence: 99%

A molecular signature in the pannexin1 intracellular loop confers channel activation by the α1 adrenoreceptor in smooth muscle cells

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…Measurement of tissue superoxide level was performed as previously described 14 . Briefly, approximately 5 mg of tissue was added to oxygenated KREBS-HEPES buffer (KREBS-HENSELEIT buffer (Sigma, K3753) plus 25 mmol/L NaHCO 3 , 20 mmol/L Sodium HEPES, 2.5 mmol/L CaCl 2 , pH= 7.2–7.4) and incubated at 37°C for 30 minutes.…”

Section: Methodsmentioning

confidence: 99%

Modulating Vascular Hemodynamics With an Alpha Globin Mimetic Peptide (HbαX)

et al. 2016

Self Cite

View full text Add to dashboard Cite

The ability of hemoglobin to scavenge the potent vasodilator nitric oxide in the blood has been well established as a mechanism of vascular tone homeostasis. In endothelial cells, the alpha chain of hemoglobin (hereafter, alpha globin) and endothelial nitric oxide synthase form a macromolecular complex, providing a sink for nitric oxide directly adjacent to the production source. We have developed an alpha globin mimetic peptide (named HbαX) that displaces endogenous alpha globin and increases bioavailable nitric oxide for vasodilation. Here we show that, in vivo, HbαX administration increases capillary oxygenation and blood flow in arterioles acutely and produces a sustained decrease in systolic blood pressure in normal and angiotensin II-induced hypertensive states. HbαX acts with high specificity and affinity to endothelial nitric oxide synthase, without toxicity to liver, kidney, and no effect on p50 of O2 binding in red blood cells. In human vasculature, HbαX blunts vasoconstrictive response to cumulative doses of phenylephrine, a potent constricting agent. By binding to endothelial nitric oxide synthase and displacing endogenous alpha globin, HbαX modulates important metrics of vascular function, increasing vasodilation and flow in the resistance vasculature.

show abstract

“…A recent report by Cechova et al suggests collectrin directly regulates l-arginine uptake in endothelial cells leading to endothelial NOS coupling. Lack of collectrin led to vascular dysfunction, exaggerated salt sensitivity and impaired pressure natriuresis and hypertension (42). …”

Section: Angiotensin Converting Enzymementioning

confidence: 99%

Classical Renin‐Angiotensin System in Kidney Physiology

Sparks

Crowley

Gurley

et al. 2014

Comprehensive Physiology

445

429

View full text Add to dashboard Cite

The renin-angiotensin system has powerful effects in control of the blood pressure and sodium homeostasis. These actions are coordinated through integrated actions in the kidney, cardio-vascular system and the central nervous system. Along with its impact on blood pressure, the renin-angiotensin system also influences a range of processes from inflammation and immune responses to longevity. Here, we review the actions of the “classical” renin-angiotensin system, whereby the substrate protein angiotensinogen is processed in a two-step reaction by renin and angiotensin converting enzyme, resulting in the sequential generation of angiotensin I and angiotensin II, the major biologically active renin-angiotensin system peptide, which exerts its actions via type 1 and type 2 angiotensin receptors. In recent years, several new enzymes, peptides, and receptors related to the renin-angiotensin system have been identified, manifesting a complexity that was previously unappreciated. While the functions of these alternative pathways will be reviewed elsewhere in this journal, our focus here is on the physiological role of components of the “classical” renin-angiotensin system, with an emphasis on new developments and modern concepts.

show abstract

Loss of Collectrin, an Angiotensin-Converting Enzyme 2 Homolog, Uncouples Endothelial Nitric Oxide Synthase and Causes Hypertension and Vascular Dysfunction

Cited by 38 publications

References 50 publications

A molecular signature in the pannexin1 intracellular loop confers channel activation by the α1 adrenoreceptor in smooth muscle cells

A molecular signature in the pannexin1 intracellular loop confers channel activation by the α1 adrenoreceptor in smooth muscle cells

Modulating Vascular Hemodynamics With an Alpha Globin Mimetic Peptide (HbαX)

Classical Renin‐Angiotensin System in Kidney Physiology

Contact Info

Product

Resources

About