Capillary rarefaction and abnormal cardiovascular reactivity in hypertension

Ciuffetti, Giovańni; Schillaci, Giuseppe; Innocente, Salvatore; Lombardini, Rita; Pasqualini, Leonella; Notaristefano, Salvatore; Mannarino, Elmo

doi:10.1097/00004872-200312000-00018

Cited by 39 publications

(30 citation statements)

References 24 publications

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“…Hence, isoprostanes may contribute to development of capillary rarefaction, which has been observed in pathophysiological states of increased oxidative stress, such as CHD or systemic hypertension. 19,20 In our study, 8-iso-PGF 2␣ , 8-iso-PGA 2 , and 8-iso-PGE 2 inhibited the VEGF-induced angiogenic response via activation of the TBXA2R, because the TBXA2R antagonists SQ-29548, BM 567, and ICI 192,605 reversed isoprostaneinduced inhibition of angiogenesis (online data supplement). Besides pharmacological antagonism of the TBXA2R, we were able to demonstrate that lentiviral knockdown of TBXA2R also resolved the inhibitory effect of 8-iso-PGF 2␣ (online data supplement).…”

Section: Discussionmentioning

confidence: 56%

“…17,18 Moreover, several groups have demonstrated that patients at high cardiovascular risk, eg, hypertensive individuals, or patients with established CHD exhibit an impaired response to angiogenic stimuli and a rarefaction of the peripheral microvascular (capillary) bed. 19,20 Because recent experimental findings have indicated that synthetic TBXA2R mimetics may inhibit crucial steps of the angiogenesis, eg, the sprouting of new vessels from preexisting vessels, 21,22 we hypothesized that isoprostanes may contribute to vascular rarefaction by inhibiting angiogenesis via activation of the TBXA2R.…”

mentioning

confidence: 99%

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Isoprostanes Inhibit Vascular Endothelial Growth Factor–Induced Endothelial Cell Migration, Tube Formation, and Cardiac Vessel Sprouting In Vitro, As Well As Angiogenesis In Vivo via Activation of the Thromboxane A ₂ Receptor

Benndorf

Schwedhelm

Gnann

et al. 2008

Circulation Research

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Abstract-Isoprostanes are endogenously formed end products of lipid peroxidation. Furthermore, they are markers of oxidative stress and independent risk markers of coronary heart disease. In patients experiencing coronary heart disease, impaired angiogenesis may exacerbate insufficient blood supply of ischemic myocardium. We therefore hypothesized that isoprostanes may exert detrimental cardiovascular effects by inhibiting angiogenesis. We studied the effect of isoprostanes on vascular endothelial growth factor (VEGF)-induced migration and tube formation of human endothelial cells (ECs), and cardiac angiogenesis in vitro as well as on VEGF-induced angiogenesis in the chorioallantoic membrane assay in vivo. The isoprostanes 8-iso-PGF 2␣ , 8-iso-PGE 2 , and 8-iso-PGA 2 inhibited VEGF-induced migration, tube formation of ECs, and cardiac angiogenesis in vitro, as well as VEGF-induced angiogenesis in vivo via activation of the thromboxane A 2 receptor (TBXA2R): the specific TBXA2R antagonists SQ-29548, BM 567, and ICI 192,605 but not the thromboxane A 2 synthase inhibitor ozagrel blocked the effect of isoprostanes. The isoprostane 8-iso-PGA 2 degraded into 2 biologically active derivatives in vitro, which also inhibited EC tube formation via the TBXA2R. Moreover, short hairpin RNA-mediated knockdown of the TBXA2R antagonized isoprostane-induced effects. In addition, Rho kinase inhibitor Y-27632 reversed the inhibitory effect of isoprostanes and the thromboxane A 2 mimetic U-46619 on EC migration and tube formation. Finally, the various isoprostanes exerted a synergistic inhibitory effect on EC tube formation. We demonstrate for the first time that isoprostanes inhibit angiogenesis via activation of the TBXA2R. By this mechanism, isoprostanes may contribute directly to exacerbation of coronary heart disease and to capillary rarefaction in disease states of increased oxidative stress.

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Section: Discussionmentioning

confidence: 56%

mentioning

confidence: 99%

Isoprostanes Inhibit Vascular Endothelial Growth Factor–Induced Endothelial Cell Migration, Tube Formation, and Cardiac Vessel Sprouting In Vitro, As Well As Angiogenesis In Vivo via Activation of the Thromboxane A ₂ Receptor

Benndorf

Schwedhelm

Gnann

et al. 2008

Circulation Research

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“…Hypertension, a known complication of VEGFR signalling inhibition, is likely related with several factors, including diminished nitric oxide and prostacyclin synthesis (Scotland et al, 2005), diminished endothelial baroreceptor response (Yang et al, 2002), small artery and arteriole rarefaction (Ciuffetti et al, 2003) as well as increased vascular stiffness (Veronese et al, 2006). To our knowledge, this is the first clinical trial among malignant glioma patients to note an association between hypertension after VEGF-targeted therapy and improved outcome.…”

Section: Discussionmentioning

confidence: 84%

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study

et al. 2009

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BACKGROUND: We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial. METHODS: A total of59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg À1 bevacizumab biweekly and 50 mg m À2 etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2a (HIF-2a) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome. RESULTS: Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade X3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism. CONCLUSION: Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430).

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“…5 Substantial evidence indicates that microvascular rarefaction is associated with the pathogenesis of hypertension and may be accompanied by parenchymal cell death. 6,7 The disappearance of microvessels in hypertensive subjects may be a secondary event after blood pressure elevation. 8 However, recent research in man demonstrates microvascular rarefaction in pre-established stage of hypertensive subjects who still maintain near normal blood pressure.…”

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confidence: 99%

Oxidative Stress Promotes Endothelial Cell Apoptosis and Loss of Microvessels in the Spontaneously Hypertensive Rats

Kobayashi

DeLano

Schmid‐Schönbein

2005

ATVB

116

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Objective-Endothelial cell apoptosis caused by oxidative stress may lead to the loss of microvessels (rarefaction) in hypertension. We examine here the effects of antioxidants on cell apoptosis and rarefaction. Methods and Results-The juvenile spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were treated with superoxide scavengers, Tempol or Tiron, during growth. After the treatment, oxidative stress status, endothelial cell apoptosis rate, and microvessel length density in skeletal muscle and mesentery were evaluated in comparison with age-matched controls. Untreated 16-week-old SHR had higher oxidative stress (PϽ0.01) and cell apoptosis rate (PϽ0.05) and lower microvessel length density (371Ϯ17 mm/mm 3 [PϽ0.01]) compared with age-matched WKY rats (435Ϯ15 mm/mm 3 ). In the SHR, but not in WKY rats, systemically applied antioxidants attenuated oxidative stress and cell apoptosis rate (PϽ0.05 versus untreated controls) and prevented the loss of microvessels (411Ϯ15 Key Words: arterial hypertension Ⅲ capillary Ⅲ endothelial cell apoptosis Ⅲ microvessels Ⅲ oxidative stress Ⅲ rarefaction Ⅲ superoxide A number of hypertensive animal models 1-3 and patients with essential hypertension 4 exhibit a reduction in microvessel length density in tissues such as skeletal muscle, skin, conjunctiva, and myocardium. This phenomenon, designated as structural or anatomic rarefaction, leads to an increase in peripheral vascular resistance and localized reduction in oxygen delivery to the tissue. 5 Substantial evidence indicates that microvascular rarefaction is associated with the pathogenesis of hypertension and may be accompanied by parenchymal cell death. 6,7 The disappearance of microvessels in hypertensive subjects may be a secondary event after blood pressure elevation. 8 However, recent research in man demonstrates microvascular rarefaction in pre-established stage of hypertensive subjects who still maintain near normal blood pressure. 9 In addition, the loss of microvessels is implicated in development of nonhypertensive pathologic conditions including diabetic organ failure. 10 These findings seem to suggest that factors other than elevated arterial pressure may promote the disappearance of microvessels. Accumulating evidence indicates that the increase in endothelial cell apoptosis in microvessels may cause rarefaction in hypertensive subjects, although the mechanism of enhanced cell apoptosis is still undergoing investigation. 11,12 We hypothesize that oxidative stress promotes endothelial cell apoptosis in microvessels and induces rarefaction in the spontaneously hypertensive rats (SHR). In the SHR, microvascular endothelium is exposed to enhanced oxidative stress due to an increase in xanthine-oxidase 13 and NADPH-oxidase activity 14 and/or a reduction in superoxide-dismutase activity. 15 Reactive oxygen species (ROS) modulate diverse functions and exert secondary effects on microvessels, eg, an inhibition of endothelium-dependent vasodilation 16 and a promotion of leukocyte adhesion to e...

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Capillary rarefaction and abnormal cardiovascular reactivity in hypertension

Abstract: A reduced microvascular network may contribute to abnormal cardiovascular reactivity and to exercise-induced rheological abnormalities in hypertension.

Cited by 39 publications

References 24 publications

Isoprostanes Inhibit Vascular Endothelial Growth Factor–Induced Endothelial Cell Migration, Tube Formation, and Cardiac Vessel Sprouting In Vitro, As Well As Angiogenesis In Vivo via Activation of the Thromboxane A ₂ Receptor

Isoprostanes Inhibit Vascular Endothelial Growth Factor–Induced Endothelial Cell Migration, Tube Formation, and Cardiac Vessel Sprouting In Vitro, As Well As Angiogenesis In Vivo via Activation of the Thromboxane A ₂ Receptor

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study

Oxidative Stress Promotes Endothelial Cell Apoptosis and Loss of Microvessels in the Spontaneously Hypertensive Rats

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Capillary rarefaction and abnormal cardiovascular reactivity in hypertension

Abstract: A reduced microvascular network may contribute to abnormal cardiovascular reactivity and to exercise-induced rheological abnormalities in hypertension.

Cited by 39 publications

References 24 publications

Isoprostanes Inhibit Vascular Endothelial Growth Factor–Induced Endothelial Cell Migration, Tube Formation, and Cardiac Vessel Sprouting In Vitro, As Well As Angiogenesis In Vivo via Activation of the Thromboxane A 2 Receptor

Isoprostanes Inhibit Vascular Endothelial Growth Factor–Induced Endothelial Cell Migration, Tube Formation, and Cardiac Vessel Sprouting In Vitro, As Well As Angiogenesis In Vivo via Activation of the Thromboxane A 2 Receptor

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study

Oxidative Stress Promotes Endothelial Cell Apoptosis and Loss of Microvessels in the Spontaneously Hypertensive Rats

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Isoprostanes Inhibit Vascular Endothelial Growth Factor–Induced Endothelial Cell Migration, Tube Formation, and Cardiac Vessel Sprouting In Vitro, As Well As Angiogenesis In Vivo via Activation of the Thromboxane A ₂ Receptor

Isoprostanes Inhibit Vascular Endothelial Growth Factor–Induced Endothelial Cell Migration, Tube Formation, and Cardiac Vessel Sprouting In Vitro, As Well As Angiogenesis In Vivo via Activation of the Thromboxane A ₂ Receptor