Expression of Cyr61 in ApoE−/− mice with chronic unilateral renal artery ligation

AbstractCyr61 is a member of the CCN family of proteins that is expressed in atherosclerotic lesions and regulated by angiotensin II. It is unknown whether renal artery stenosis (RAS) increases Cyr61 expression. Male ApoE−/− mice were randomized to surgically induced RAS, RAS + treatment with either irbesartan, aliskiren or amlodipine or sham-surgery. RAS resulted in increased plasma angiotensin II levels, a mild, sustained increase in systolic blood pressure and increased aortic lipid deposition compared to sham-surgery. Surgically induced RAS led to the formation of atheroma in the infrarenal aorta and there was consistent and intense staining for Cyr61 within the atheroma. Treatment with irbesartan, aliskiren and amlodipine were associated with decreased aortic lipid deposition and decreased staining for Cyr61 in aortic atheroma. Serum levels of Cyr61 were not increased in mice or humans with RAS. In summary, Cyr61 expression in aortic atheroma but not serum is increased by RAS in ApoE−/− mice and is reduced by agents that lower blood pressure.

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Abstract 542: Upregulation of Cyr 61 Expression in Atherosclerosis Is Mediated by β3 Integrins

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a542 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

Alokkumar S Pathak ◽

Jianhua Huang ◽

Mauricio Rojas ◽

George Stouffer

Keyword(s):

Blood Pressure ◽

Aortic Arch ◽

Lipid Deposition ◽

Mrna Levels ◽

Ang Ii ◽

Intense Staining ◽

Descending Aorta ◽

Sham Surgery ◽

Β3 Integrin ◽

Sustained Increase

Objective: Cyr 61 is a member of the CCN family of proteins that is expressed in atherosclerotic lesions, stimulates proliferation of cultured smooth muscle cells (SMC) and is upregulated by angiotensin II (Ang II). We studied whether Ang II inhibition decreased expression of Cyr 61 in atheromas of ApoE–/– mice with unilateral partial renal artery ligation (RAL). Methods and Results: 18 week old ApoE–/– mice were randomized to unilateral RAL, RAL + treatment with irbesartan, RAL + treatment with aliskiren or sham-surgery for 90 days. RAL reduced blood flow (60 ± 6% of baseline values), resulted in a sustained increase in renin mRNA levels in the ligated kidney, and elicited a mild, sustained increase in systolic blood pressure (11% increase in weighted average of blood pressure) compared to sham-surgery. Treatment with irbesartan or aliskiren prevented the hypertensive response. Lipid deposition, measured by Oil-red O staining 90 days after surgery, was increased approximately 3 fold following RAL in both the aortic arch and in the descending aorta compared to sham-surgery. Treatment with irbesartan or aliskiren reduced the aortic arch and descending aorta lipid deposition to a level that was statistically similar to sham-surgery. Atheromas in the abdominal aorta showed intense staining for Cyr 61 in RAL mice but patchy, diffuse and less intense staining in RAL + irbesartan (43% less staining) and RAL + aliskiren (60% less staining) mice. Studies in RASMC showed that Cyr 61 was secreted in response to treatment with Ang II and that echistatin, a function-blocking disintegrin that binds αvβ3 integrins on SMC, reduced Cyr 61 induced proliferation of RASMC. In mice with RAL, atheromas showed generalized and intense staining for β3 integrins that co-localized with Cyr 61. In contrast, β3 integrin staining was localized, discrete and even non-existent in atheromas from RAL + irbesartan and RAL + aliskiren mice. Sham-surgery mice had no atheromas and minimal staining for Cyr 61 and β3 integrins. Conclusions: Unilateral RAL resulted in a marked increase in Cyr 61 and β3 integrin expression within atheromas. Treatment with irbesartan or aliskiren significantly reduced aortic lipid deposition, and expression of Cyr 61 and β3 integrins in atheromas.

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Effect of sinoaortic denervation on pressor responses in pregnant rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1992.262.6.r1100 ◽

1992 ◽

Vol 262 (6) ◽

pp. R1100-R1105 ◽

Cited By ~ 6

Author(s):

T. Hines ◽

W. M. Barron

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Angiotensin Ii ◽

Mean Arterial Pressure ◽

Arterial Baroreflex ◽

Pregnant Rats ◽

Pregnant Rat ◽

Sham Surgery ◽

Pressor Responses ◽

Vascular Sensitivity

We tested the hypothesis that augmented arterial baroreflex activity contributes to attenuation of pressor responses in intact pregnant animals by comparing changes in blood pressure and heart rate during infusions of angiotensin II, phenylephrine, and vasopressin in chronically instrumented pregnant and virgin rats approximately 5 wk after sinoaortic denervation (SAD) or sham surgery. Baseline mean arterial pressure was significantly lower in pregnant animals in both the sham-operated (pregnant 91.7 +/- 1.7 mmHg, virgin 103.7 +/- 2.5 mmHg) and SAD states (pregnant 107.3 +/- 4.0 mmHg, virgin 114.1 +/- 4.0 mmHg). Pressor responses to all three agents were significantly blunted in pregnant animals compared with similarly treated virgins, with the magnitude of attenuation similar in both sham and SAD states. Heart rate decreased similarly in reflex-intact pregnant and virgin animals during pressor infusions. These findings suggest that attenuated pressor responses in the pregnant rat are due primarily to mechanisms other than augmentation of arterial baroreflex activity and are consistent with a generalized reduction in vascular sensitivity during gestation.

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Inhibition of angiotensin II Gq signaling augments β-adrenergic receptor mediated effects in a renal artery stenosis model of high blood pressure

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2008.09.708 ◽

2009 ◽

Vol 46 (1) ◽

pp. 100-107 ◽

Cited By ~ 5

Author(s):

David M. Harris ◽

Xiongwen Chen ◽

Stéphanie Pesant ◽

Heather I. Cohn ◽

Scott M. MacDonnell ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Renal Artery ◽

Renal Artery Stenosis ◽

High Blood Pressure ◽

Adrenergic Receptor ◽

Artery Stenosis ◽

Mediated Effects

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Changes of Plasma and Cerebrospinal Fluid Noradrenaline during Frusemide Administration and Acute Renal Artery Constriction in Dogs

Clinical Science ◽

10.1042/cs063343s ◽

1982 ◽

Vol 63 (s8) ◽

pp. 343s-345s ◽

Cited By ~ 1

Author(s):

Yoshiaki Masuyama ◽

Yuji Ueno ◽

Mikio Arita ◽

Hidetoshi Suruda ◽

Osamu Mohara

Keyword(s):

Blood Pressure ◽

Cerebrospinal Fluid ◽

Nervous System ◽

Angiotensin Ii ◽

Renal Artery ◽

Arterial Blood Pressure ◽

Plasma Noradrenaline ◽

Direct Role ◽

Arterial Blood ◽

Renal Artery Constriction

1. The effects of circulating angiotensin II on cerebrospinal fluid and plasma noradrenaline during frusemide administration and acute renal artery constriction were studied in dogs. 2. The administration of frusemide produced significant increases in cerebrospinal fluid and plasma noradrenaline. Intravertebral artery infusion of [Sar1, Ala8]angiotensin II (saralasin) significantly suppressed the frusemide-induced increases in cerebrospinal and plasma noradrenaline and resulted in a fall in arterial blood pressure. 3. Acute renal artery constriction produced the marked elevation of plasma noradrenaline and arterial blood pressure, although no significant increase was found in cerebrospinal fluid noradrenaline. Though intravertebral artery infusion of saralasin did not affect cerebrospinal fluid and plasma noradrenaline, intravenous infusion of saralasin reduced the increases in arterial blood pressure and plasma noradrenaline induced by acute renal artery constriction. 4. Plasma volume was significantly reduced by frusemide administration, but unchanged by acute renal artery constriction. 5. Therefore it is suggested that circulating angiotensin II may contribute to the regulation of blood pressure at least partially by acting on the central nervous system in the sodium- and volume-depleted states. However, the renin-angiotensin system appears to play a rather direct role in the mechanism of hypertension induced by renal artery constriction, not through the action of angiotensin II on the central sympathetic nervous system.

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Abstract 418: Microfibrillar-Associated Protein 4 Deficiency Reduces Size and Incidence Rate of Angiotensin II Induced Abdominal Aortic Aneurysms in Mice

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.418 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Katrine L Kirketerp-Møller ◽

Jane Stubbe ◽

Anders Schlosser ◽

Karin Kejling ◽

Jesper B Møller ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Incidence Rate ◽

Aortic Aneurysms ◽

Aortic Tissue ◽

Aortic Blood Flow ◽

Infrarenal Aorta ◽

Arterial Blood ◽

Elastin Degradation ◽

Abdominal Aortic

Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix (ECM) protein primarily located in elastic arteries. It can bind elastin and collagen, and furthermore activate vascular cells through cellular integrin binding and modulate matrix metalloprotinase (MMP) activity. We hypothesized that lack of MFAP4 would decrease vascular inflammation and abdominal aortic aneurysm (AAA) formation. AAA was induced in 9-11 week old mice using two experimental mouse models: 1) Male Mfap4 -/- /ApoE -/- double knock-out (dKO) and ApoE -/- littermate control mice were feed western diet and subjected to continuously angiotensin II (AngII, 1000 ng/kg/min) infusion for 9-28 days via subcutaneous osmotic mini-pumps. Arterial blood pressure was measured in the femoral artery. 2) 1.5 U/mL elastase was infused into the infrarenal aorta in Mfap4 -/- and littermate Mfap4 +/+ mice for 5 minutes. Aortic blood flow was restored and the mice recovered for 9-16 days. Aortic diameter was measured in mice subjected to AngII or elastase infusion at day 28 and 16 respectively. MMP activity was detected by zymography. No difference in AAA formation was observed between genotypes after elastase perfusion. In response to AngII infusion dKO mice showed a significantly decrease in AAA diameter and incidence rate compared to ApoE -/- mice. AngII-induced increase in blood pressure was not dependent of MFAP4. However, there was decreased aortic arch atherosclerotic plaque formation, MMP2 and MMP9 activity in aortic tissue from dKO mice compared to ApoE -/- mice. Furthermore there was a non-significant tendency of decreased elastin degradation score in the AngII infused dKO mice, however this was not observed in the elastase perfused mice. Activity of MMP12 and extent of infiltrating leukocytes in aneurysmal tissue from both models will be further investigated. In conclusion we observed a decreased AAA formation and MMP activity in Mfap4 -/- /ApoE -/- mice which was not explained by variation in blood pressure or altered elastin degradation. The data suggest that MFAP4 induces MMP2-activity and thus the propensity for AAA formation.

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Blood pressure and plasma angiotensin II concentration after renal artery constriction and angiotensin infusion in the dog. (5-Isoleucine)angiotensin II and its breakdown fragments in dog blood.

Circulation Research ◽

10.1161/01.res.38.4.315 ◽

1976 ◽

Vol 38 (4) ◽

pp. 315-321 ◽

Cited By ~ 38

Author(s):

A M Caravaggi ◽

G Bianchi ◽

J J Brown ◽

A F Lever ◽

J J Morton ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Renal Artery ◽

Plasma Angiotensin ◽

Dog Blood ◽

Renal Artery Constriction

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Effect of Unclipping on Pressor Responses in Rats with Renovascular Hypertension

Clinical Science ◽

10.1042/cs0660473 ◽

1984 ◽

Vol 66 (4) ◽

pp. 473-480 ◽

Cited By ~ 4

Author(s):

Robert F. Bing ◽

John D. Swales ◽

David Taverner ◽

Herbert Thurston

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Renal Artery ◽

Renovascular Hypertension ◽

Plasma Renin ◽

Chronic Hypertension ◽

Hypertensive Rats ◽

Plasma Renin Concentration ◽

Pressor Responses

1. Pressor responses to angiotensin II and noradrenaline have been examined in two models of renovascular hypertension (two-kidney one-clip and one-kidney one-clip) before and 24 h after removal of the renal artery clip to examine the possible role of pressor hyper-responsiveness in the maintenance of hypertension. Early and chronic hypertension was studied to assess the part played by progressive structural hypertrophy. 2. Plasma renin concentration was elevated in early two-kidney hypertensive rats, whereas it was similar to that in age-matched normal rats in early one-kidney and chronic two-kidney hypertensive rats. Twenty-four hours after unclipping plasma renin concentration was the same in all groups. Unclipping restored blood pressure to normal levels by 24 h, whereas sham-operated animals remained hypertensive. 3. Angiotensin II responses in both early and chronic two-kidney one-clip hypertensive rats were lower than in age-matched normal rats. In unclipped rats responses were similar to those in normals. One-kidney hypertensive rats had similar angiotensin II responses to normal rats and there was no change with unclipping. Blockade of endogenous angiotensin II production by converting enzyme inhibition resulted in similar angiotensin II responses in hypertensive and unclipped groups. 4. In normal rats, angiotensin II responses were inversely related to plasma renin concentration (r = −0.47, P<0.001). Angiotensin II responses in hypertensive and unclipped rats were found to show a similar relationship to plasma renin concentration as normal rats. 5. Noradrenaline responses in hypertensive rats were similar to those in age-matched normals and there was no significant change with unclipping. In normal rats there was no relationship between noradrenaline responses and plasma renin concentration (r = −0.11, P<0.5). 6. These results emphasize the importance of the activity of endogenous renin-angiotensin in determining angiotensin II responses in vivo. It is concluded that neither the maintenance of hypertension nor the fall in blood pressure produced by removal of the renal artery clip in renovascular hypertension is due to changes in responsiveness to angiotensin II.

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