Essential Role of Vascular Endothelial Growth Factor in Angiotensin II–Induced Vascular Inflammation and Remodeling

Zhao, Qingwei; Ishibashi, Masayoshi; Hiasa, Kenichi; Tan, Chunyan; Takeshita, Akira; Egashira, Kensuke

doi:10.1161/01.hyp.0000138688.78906.6b

Cited by 165 publications

(120 citation statements)

References 50 publications

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“…Angiotensin II up-regulates VEGF mRNA expression in vascular and renal cells (VSMCs, endothelial cells, cardiac myofibroblasts, mesangial cells), primarily through the AT1 receptor. This involvement of Ang II in the early phase of vascular inflammation is mediated independently of hemodynamic changes [47].…”

Section: Part II -Role Of the Renin-angiotensin-aldosterone System Onmentioning

confidence: 99%

Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation

Raimondo¹,

Tuttolomondo²,

Buttà³

et al. 2012

CPD

106

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Abstract:The role of inflammation in cardiovascular disease and in hypertensive disease above all, is complex. Several studies confirm that activation of renin-angiotensin-aldosteron system (RAAS), through increase in the production of angiotensin II (Ang II), is closely related to local vascular inflammation. Over the BP lowering effects of anti-hypertensive treatments, several ancillary effects for every class may be found, distinguishing the various drugs from one another. Given the pro-inflammatory effects of Ang II and aldosterone, agents that interfere with the components of RAAS, such as ACE inhibitors, Angiotensin Recpetor Blockers (ARBs), and mineralocorticoid receptor antagonists (spironolactone or the more selective eplerenone), represent logical therapeutic tools to reduce vascular inflammation and cardiovascular risk, as suggested in large clinical trials in patients with hypertension and diabetes. Regarding ACE inhibitors, actually there is no convincing evidence indicating that ACEi's reduce plasma levels of major inflammatory markers in hypertension models. Lack of evidence concerns especially these inflammation markers, such as fibrinogen of CRP, which are less closely related to atherosclerotic disease and vascular damage and conversely are affected by several more aspecific factors. Results obtained by trials accomplished using ARBs seem to be more univocal to confirm, although to great extent, these is an anti-inflmmatory effect of drugs bocking AT1 receptor. In order to strictly study the effects of blockage of RAAS on inflammation, future studies may explore different strategies by, for example, simultaneously acting on the ACE and the AT1 angiotensin receptors.

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Section: Part II -Role Of the Renin-angiotensin-aldosterone System Onmentioning

confidence: 99%

Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation

Raimondo¹,

Tuttolomondo²,

Buttà³

et al. 2012

CPD

106

View full text Add to dashboard Cite

show abstract

“…Furthermore, we did not find any difference in the inflammatory biomarkers in type 1 diabetic patients who were treated with blood pressure-lowering drugs compared with the normotensive patients. It is known that angiotensin II may stimulate IL-6 and other inflammatory biomarkers (20,21). Thus, it is possible that administration of angiotensin II blockers, as given to six patients, would reduce the levels of inflammatory biomarkers.…”

Section: Correlation Between Inflammatory Indicators and Metabolic Mementioning

confidence: 99%

Type 1 Diabetes Is Associated With Increased Cyclooxygenase- and Cytokine-Mediated Inflammation

et al. 2005

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OBJECTIVE -The extent of involvement of cyclooxygenase (COX)-mediated inflammation in type 1 diabetes is unknown, and the association between the COX-and cytokine-mediated inflammatory responses in type 1 diabetes is not fully understood.RESEARCH DESIGN AND METHODS -Plasma high-sensitivity C-reactive protein (CRP), 24-h urinary and plasma 15-keto-dihydro-prostaglandin F 2␣ (a metabolite of prostaglandin F 2␣ [PGF 2␣ ] and an indicator of COX-mediated inflammation), serum amyloid protein A (SAA), and interleukin (IL)-6 (indicators of inflammation) were measured in 38 subjects with type 1 diabetes and 41 healthy age-and sex-matched control subjects.RESULTS -The inflammatory indicators (urinary 15-keto-dihydro-PGF 2␣ , P Ͻ 0.01; IL-6, P Ͻ 0.04) were increased in men with diabetes. CRP and SAA did not show any significant difference between the diabetic and the control subjects. Urinary levels of 15-keto-dihydro-PGF 2␣ correlated with the degree of glycemic control, HbA 1c (r ϭ 0.42, P Ͻ 0.0005). No correlation was found between the duration of diabetes and the inflammatory biomarkers or metabolic measurements.CONCLUSIONS -These results suggest that an early low-grade inflammatory process reflected by elevated levels of PGF 2␣ and IL-6 is involved in type 1 diabetes. Thus, both COX-and cytokine-mediated inflammatory pathways are significantly related to type 1 diabetes. Diabetes Care 28:1371-1375, 2005C ompared with a control population, type 1 diabetes is associated with an increased risk of microvascular complications and premature atherosclerosis (1). Atherosclerosis is considered to be in part a consequence of a chronic lowgrade inflammation (2,3), and it has been suggested that atherosclerosis and diabetes might share the mutual inflammatory phenomenon hypothesis (4,5). In recent years inflammation has been suggested to be involved in type 1 diabetes (6). Blood levels of interleukin (IL)-6 have been shown to be normal (7) or higher (8,9) in type 1 diabetic patients compared with levels in control subjects. Cytokinemediated acute-phase proteins have also been studied (9,10), but their role in diabetes without atherosclerosis is inconclusive.An ongoing inflammatory process can lead to gradual cell destruction followed by arachidonic acid release and its bioconversion by cyclooxygenase (COX) to various bioactive prostaglandins. Prostaglandin F 2␣ (PGF 2␣ ) is a potent vasoconstrictive compound (11). Moreover, prostaglandins are important mediators of the inflammatory process (12,13), and 15-keto-dihydro-PGF 2␣ , a major metabolite of PGF 2␣ , has been shown to be a reliable indicator of in vivo COX-mediated inflammation (14,15). In a recent study, 15-keto-dihydro-PGF 2␣ , high-sensitivity C-reactive protein (CRP), and serum amyloid protein A (SAA), which are all inflammatory indicators, were increased in men with type 2 diabetes in a population-based cross-sectional study (16). Cytokine-mediated CRP and SAA were more closely related to obesity and insulin than to the diagnosis of diabetes, suggesting that COX-med...

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“…1-4 RAS activation and increased levels of AngII can be seen in patients with cardiovascular diseases, including atherosclerosis, hypertension, cardiac hypertrophy and heart failure. 1, 5,6 Conversely, inhibition of RAS activation by angiotensin receptor blockade has been shown to significantly improve patient survival and limit the progression of cardiac remodeling and heart failure. 7 Investigations in small animals have confirmed that AngII exposure can result in myocardial fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Myocardial migration by fibroblast progenitor cells is blood pressure dependent in a model of angII myocardial fibrosis

et al. 2012

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Activation of the renin-angiotensin system (RAS) is thought to promote myocardial fibrosis. However, it is unclear whether this physiological fibrotic response results from chronic hemodynamic stress or from direct cellular signaling. Male C57B/6 mice were randomly assigned to receive angiotensin II (AngII) (2.0 lg kg À1 min À1 ), AngII+hydralazine (6.9 lg kg À1 min À1 ) or saline (control) via osmotic pumps for 7 days. Blood pressure was measured via noninvasive plethysmography. Hearts were harvested and processed for analysis. Cellular infiltration and collagen deposition were analyzed using histological staining. Molecular mediators were assessed using quantitative RT-PCR. As previously described, animals that received AngII developed hypertension and multifocal cellular infiltration by SMA + /CD133 + fibroblast progenitors followed by collagen deposition. The coadministration of hydralazine with AngII completely inhibited the hypertensive effects of AngII (Pp0.01) and resulted in minimal cellular infiltration and minimal collagen deposition. These findings were in the context of persistent RAS activation, which was evidenced by elevation in serum aldosterone levels in animals that received AngII or AngII+hydralazine compared with animals that received saline. At the molecular level, infusion of AngII resulted in the significant upregulation of profibrotic factors (connective tissue growth factor-7.8±0.7 fold), proinflammatory mediators (TNFa-4.6±0.8 fold; IL-1b-6.4±2.6 fold) and chemokines (CCL2-3.8 ± 1.0 fold; CXCL12-3.2 ± 0.4 fold), which were inhibited when hydralazine was also infused. We provide evidence that myocardial infiltration by fibroblast progenitor cells secondary to AngII and the resultant fibrosis can be prevented by the addition of hydralazine. Furthermore, the beneficial effects of hydralazine were observed while maintaining RAS activation, suggesting that the mechanism of fibrosis is blood pressure dependent.

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Essential Role of Vascular Endothelial Growth Factor in Angiotensin II–Induced Vascular Inflammation and Remodeling

Cited by 165 publications

References 50 publications

Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation

Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation

Type 1 Diabetes Is Associated With Increased Cyclooxygenase- and Cytokine-Mediated Inflammation

Myocardial migration by fibroblast progenitor cells is blood pressure dependent in a model of angII myocardial fibrosis

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