Effect of hypoxia and endothelial loss on vascular smooth muscle cell responsiveness to VEGF-A: role of flt-1/VEGF-receptor-1

Parenti, Astrid; Brogelli, Laura; Filippi, Sandra; Donnini, Sandra; Ledda, F.

doi:10.1016/s0008-6363(02)00326-7

Cited by 60 publications

(60 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PAI-1 and TGF-β interfere with liver regeneration by suppressing hepatocyte growth factor (38). Although VEGF-A usually acts as a vasodilator, it can act as a vasoconstrictor under conditions of endothelial failure and hepatic sinusoidal injury (39). Platelet aggregation in the space of Disse may explain many of the symptoms, venous perfusion abnormalities, and portal hypertension detected in SOS, findings that cannot be confirmed pathologically.…”

Section: Discussionmentioning

confidence: 99%

Extravasated platelet aggregation in the livers of rats with drug-induced hepatic sinusoidal obstruction syndrome

Hirata

Tajima

Miyashita

et al. 2017

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. Oxaliplatin-based chemotherapy plays an important role in the treatment of colorectal liver metastases. Oxaliplatin, however, causes sinusoidal obstruction syndrome (SOS), which is characterized by portal hypertension, splenomegaly, thrombocytopenia, and liver dysfunction. SOS is diagnosed histopathologically by disruption of the sinusoidal endothelium, collagen deposition, fibrosis especially around zone 3, dilatation of the sinusoidal space and congestion. This study assessed the characteristics of a rat model of SOS. SOS was induced in rats by administration of monocrotaline (MCT). Blood chemistries and macroscopic and microscopic findings were compared in rats administered MCT and vehicle (control group). Levels of expression in the liver of CD41, P-selectin, rat endothelial cell antigen-1, CD34, and cleaved caspase-3 were analyzed immunohistochemically. Moreover, livers of these rats were analyzed by electron microscopy. Macroscopically, MCT-treated rats showed accumulation of bloody ascites and blue liver and were diagnosed with SOS histologically. Serum concentrations of aspartate aminotransferase (P=0.003), alanine aminotransferase (P=0.008), total-bilirubin (P=0.012), direct-bilirubin (P=0.007), indirect-bilirubin (P=0.003), lactate dehydrogenase (P<0.001) and hyaluronic acid (P=0.016) were significantly higher, and platelet counts significantly lower (P=0.004), in MCT-treated than in control rats. The livers of MCT-treated rats were immunohistochemically positive for CD41 and P-selectin, suggesting platelet aggregates; for rat endothelial cell antigen-1 and CD34, suggesting sinusoidal endothelial disorder; and for cleaved caspase-3, suggesting hepatocyte apoptosis. Electron microscopic findings revealed platelet aggregation in the space of Disse in the MCT group. Extravasated platelet aggregation in Disse's space may be involved in the development of SOS.

show abstract

Section: Discussionmentioning

confidence: 99%

Extravasated platelet aggregation in the livers of rats with drug-induced hepatic sinusoidal obstruction syndrome

Hirata

Tajima

Miyashita

et al. 2017

Molecular Medicine Reports

View full text Add to dashboard Cite

show abstract

“…PAI-1 and TGF-β interfere with liver regeneration by suppressing hepatocyte growth factor (21). VEGF-A, which usually acts as a vasodilator, may paradoxically act as a vasoconstrictor under conditions of endothelial failure (22). Moreover, bevacizumab, an antibody against VEGF-A, was found to protect against SOS in patients administered oxaliplatin-based chemotherapy for CRLM (23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

Oxaliplatin-based chemotherapy induces extravasated platelet aggregation in the liver

Tajima

Ohta

Miyashita

et al. 2015

Molecular and Clinical Oncology

View full text Add to dashboard Cite

Abstract.Oxaliplatin-based chemotherapy plays a central role in the treatment of patients with colorectal liver metastasis (CRLM). This treatment, however, has been associated with hepatic sinusoidal obstruction syndrome (SOS), a clinically important adverse effect characterized by a bluish hue of the liver, splenomegaly and thrombocytopenia, resulting in liver dysfunction. The significant association between the sinusoidal endothelium and platelets has suggested that oxaliplatin-based chemotherapy affects platelets in the liver. This study compared platelet counts in patients who did and did not receive oxaliplatin-based neoadjuvant chemotherapy (NAC). The peripheral blood platelet count was significantly lower in the NAC group (n=17) compared to that in the non-NAC, or control group (n=15) (P<0.05). The spleen index was also higher in the NAC group, although the difference was not significant. However, the spleens of the patients in the NAC group were significantly enlarged following treatment (P<0.01). Immunostaining for the platelet surface marker CD42b (glycoprotein Ib), revealed more platelets in the liver in the NAC compared to the control group, particularly in the centrilobular zone III, adjacent to the hepatic central vein and in contact with hepatocytes (P<0.01). The platelets present in the spaces of Disse, referred to as extravasated platelet aggregation (EPA), secrete a number of growth factors, including transforming growth factor-β, vascular endothelial growth factor-A, plasminogen activator inhibitor-1 and thromboxane A2. In conclusion, EPA may play an important role in the development of hepatic SOS. Moreover, antiplatelet drugs may prevent the onset of SOS and hepatic injury in patients treated with oxaliplatin-based chemotherapy for CRLM.

show abstract

“…VEGF is a specific mitogen for endothelial cells, whose up-regulated expression under hypoxic conditions is necessary for the neoangiogenesis of endothelial cells 17,18) . Recently, it was reported that in cultured rat VSMCs, hypoxia induced the upregulation of VEGF-A mRNA expression, and enhanced VEGF-induced cell proliferation 10) . PDGF is reported to stimulate the proliferation of VSMCs and to be involved in vascular remodeling 19) .…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the anti-PDGF antibody slightly inhibited the incorporation of thymidine at 12 h under hypoxic conditions (data not shown). Parenti et al showed that PDGF is not significantly effective in promoting rat VSMCs growth 10) . Humar et al 21) demonstrated that the mammalian target of rapamycin (mTOR) is involved in hypoxia-triggered proliferation of VSMCs.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that the expression of VEGF is markedly enhanced by the hypoxic environment in vascular smooth muscle cells (VSMCs) [7][8][9][10] , while VEGF added to the culture medium significantly promotes cell proliferation 10) ; however, the physiological function of endogenous VEGF in autocrine regulation under hypoxic conditions has not been studied in VSMCs. Belgore et al 11) showed that VEGF-C and all VEGF receptors were present on medial VSMCs in atherosclerotic arteries.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

VEGF-Enhanced Proliferation under Hypoxia by an Autocrine Mechanism in Human Vascular Smooth Muscle Cells

Osada‐Oka

Ikeda

Imaoka

et al. 2008

JAT

View full text Add to dashboard Cite

Effect of hypoxia and endothelial loss on vascular smooth muscle cell responsiveness to VEGF-A: role of flt-1/VEGF-receptor-1

Abstract: These findings demonstrate that experimental conditions mimicking pathological vascular injury can make VSMCs responsive to VEGF-A through the induction of functional flt-1 receptors.

Cited by 60 publications

References 26 publications

Extravasated platelet aggregation in the livers of rats with drug-induced hepatic sinusoidal obstruction syndrome

Extravasated platelet aggregation in the livers of rats with drug-induced hepatic sinusoidal obstruction syndrome

Oxaliplatin-based chemotherapy induces extravasated platelet aggregation in the liver

VEGF-Enhanced Proliferation under Hypoxia by an Autocrine Mechanism in Human Vascular Smooth Muscle Cells

Contact Info

Product

Resources

About