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Local Augmented Angiotensinogen Secreted from Apoptotic Vascular Endothelial Cells Is a Vital Mediator of Vascular Remodelling.

Wu SJ, Soulez M, Yang YH, Chu CS, Shih SC, Hébert MJ, Kuo MC, Hsieh YJ - PLoS ONE (2015)

Bottom Line: After the cells were subjected to SS, we found that the mRNA expression of angiotensinogen (AGT) was increased by >3-fold in HUVECs and by approximately 2.5-fold in VSMCs.Increases in the expression of AGT protein and angiotensin II (Ang II) were found in a serum-free medium conditioned by HUVECs (SSC).In conclusion, we first demonstrated that the augmented AGT released from apoptotic endothelial cells acts as a vital progenitor of Ang II to accelerate vascular remodelling, and we suggest that blocking local augmented Ang II might be an effective strategy for restraining intimal hyperplasia.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.

ABSTRACT
Vascular remodelling is a critical vasculopathy found in atheromatous diseases and allograft failures. The local renin angiotensin system (RAS) has been implicated in vascular remodelling. However, the mechanisms by which the augmented local RAS is associated with the initial event of endothelial cell apoptosis in injured vasculature remain undefined. We induced the apoptosis of human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (VSMCs) through serum starvation (SS). After the cells were subjected to SS, we found that the mRNA expression of angiotensinogen (AGT) was increased by >3-fold in HUVECs and by approximately 2.5-fold in VSMCs. In addition, the expression of angiotensin-converting enzyme (ACE) mRNA was increased in VSMCs but decreased to 50% in HUVECs during the same apoptotic process. Increases in the expression of AGT protein and angiotensin II (Ang II) were found in a serum-free medium conditioned by HUVECs (SSC). The increased Ang II was suppressed using lisinopril (an ACE inhibitor) treatment. Moreover, the activation of ERK1/2 induced by the SSC in VSMCs was also suppressed by losartan. In conclusion, we first demonstrated that the augmented AGT released from apoptotic endothelial cells acts as a vital progenitor of Ang II to accelerate vascular remodelling, and we suggest that blocking local augmented Ang II might be an effective strategy for restraining intimal hyperplasia.

No MeSH data available.


Related in: MedlinePlus

Model of initial crosstalk among ECs and surrounding cells in vessel lesions.The paracrine source of local augmented Ang II produced from apoptotic ECs serves as a vital messenger in the formation of neointima. ECs, endothelial cells. MSCs, mesenchymal stem cells.
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pone.0132583.g006: Model of initial crosstalk among ECs and surrounding cells in vessel lesions.The paracrine source of local augmented Ang II produced from apoptotic ECs serves as a vital messenger in the formation of neointima. ECs, endothelial cells. MSCs, mesenchymal stem cells.

Mentions: Identifying the differences in AGT and ACE protein expression in the extremely thin lining of ECs in vivo is challenging, particularly when the cells undergo apoptosis. Thus, detecting the increased contents in the SSC medium was crucial. Because of the rate-limiting role of AGT in the RAS [24, 25], the release of an AGT protein as a progenitor of messengers from ECs might provide an efficient biological mechanism for informing neighbour cells to respond to apoptotic stress. ACE mRNA was suppressed in stress-induced apoptotic ECs. Although the exact mechanism through which the contrary expression of ACE and AGT genes is regulated remains unclear, it may be crucial for ECs to secrete priority mediators because ECs function on the surface of the vasculature and encounter continual and dynamic challenges from the blood stream in a vascular vessel. Nevertheless, ECs still require converting enzymes to produce Ang II peptides. Our study showed that ACE inhibitors inhibited the augmentation of Ang II in SSC, indicating that ACE or other converting enzymes are present in SSC or on the membranes of surviving HUVECs. We suggest that the amount of ACE should be sufficiently abundant in the surrounding ECs that survived to produce detectable Ang II in SSC because tissue-bound or secreted ACE has been shown to be produced by the endothelium of healthy human blood vessels [26, 27]. Moreover, consistent with previous reports indicating that increased AGT and ACE were found in the cellular structures of the neointima [21, 27, 28], we found that the mRNA expression and promoter activity of AGT and ACE genes were increased in apoptotic VSMCs. In addition, Ang II was shown to positively activate AGT expression by binding to AT1R in VSMCs [29]. Accordingly, Fig 6 shows a hypothesised model of local RAS crosstalk among ECs and their surrounding cells in vessels responding to apoptotic stress. However, the precise proportion of Ang II from the systemic or locally secreted part required to affect neointima formation requires further investigation because the synergistic contribution of AGT to its pathophysiological functions occurs in both systemic and cell-specific manners [30, 31].


Local Augmented Angiotensinogen Secreted from Apoptotic Vascular Endothelial Cells Is a Vital Mediator of Vascular Remodelling.

Wu SJ, Soulez M, Yang YH, Chu CS, Shih SC, Hébert MJ, Kuo MC, Hsieh YJ - PLoS ONE (2015)

Model of initial crosstalk among ECs and surrounding cells in vessel lesions.The paracrine source of local augmented Ang II produced from apoptotic ECs serves as a vital messenger in the formation of neointima. ECs, endothelial cells. MSCs, mesenchymal stem cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492977&req=5

pone.0132583.g006: Model of initial crosstalk among ECs and surrounding cells in vessel lesions.The paracrine source of local augmented Ang II produced from apoptotic ECs serves as a vital messenger in the formation of neointima. ECs, endothelial cells. MSCs, mesenchymal stem cells.
Mentions: Identifying the differences in AGT and ACE protein expression in the extremely thin lining of ECs in vivo is challenging, particularly when the cells undergo apoptosis. Thus, detecting the increased contents in the SSC medium was crucial. Because of the rate-limiting role of AGT in the RAS [24, 25], the release of an AGT protein as a progenitor of messengers from ECs might provide an efficient biological mechanism for informing neighbour cells to respond to apoptotic stress. ACE mRNA was suppressed in stress-induced apoptotic ECs. Although the exact mechanism through which the contrary expression of ACE and AGT genes is regulated remains unclear, it may be crucial for ECs to secrete priority mediators because ECs function on the surface of the vasculature and encounter continual and dynamic challenges from the blood stream in a vascular vessel. Nevertheless, ECs still require converting enzymes to produce Ang II peptides. Our study showed that ACE inhibitors inhibited the augmentation of Ang II in SSC, indicating that ACE or other converting enzymes are present in SSC or on the membranes of surviving HUVECs. We suggest that the amount of ACE should be sufficiently abundant in the surrounding ECs that survived to produce detectable Ang II in SSC because tissue-bound or secreted ACE has been shown to be produced by the endothelium of healthy human blood vessels [26, 27]. Moreover, consistent with previous reports indicating that increased AGT and ACE were found in the cellular structures of the neointima [21, 27, 28], we found that the mRNA expression and promoter activity of AGT and ACE genes were increased in apoptotic VSMCs. In addition, Ang II was shown to positively activate AGT expression by binding to AT1R in VSMCs [29]. Accordingly, Fig 6 shows a hypothesised model of local RAS crosstalk among ECs and their surrounding cells in vessels responding to apoptotic stress. However, the precise proportion of Ang II from the systemic or locally secreted part required to affect neointima formation requires further investigation because the synergistic contribution of AGT to its pathophysiological functions occurs in both systemic and cell-specific manners [30, 31].

Bottom Line: After the cells were subjected to SS, we found that the mRNA expression of angiotensinogen (AGT) was increased by >3-fold in HUVECs and by approximately 2.5-fold in VSMCs.Increases in the expression of AGT protein and angiotensin II (Ang II) were found in a serum-free medium conditioned by HUVECs (SSC).In conclusion, we first demonstrated that the augmented AGT released from apoptotic endothelial cells acts as a vital progenitor of Ang II to accelerate vascular remodelling, and we suggest that blocking local augmented Ang II might be an effective strategy for restraining intimal hyperplasia.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.

ABSTRACT
Vascular remodelling is a critical vasculopathy found in atheromatous diseases and allograft failures. The local renin angiotensin system (RAS) has been implicated in vascular remodelling. However, the mechanisms by which the augmented local RAS is associated with the initial event of endothelial cell apoptosis in injured vasculature remain undefined. We induced the apoptosis of human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (VSMCs) through serum starvation (SS). After the cells were subjected to SS, we found that the mRNA expression of angiotensinogen (AGT) was increased by >3-fold in HUVECs and by approximately 2.5-fold in VSMCs. In addition, the expression of angiotensin-converting enzyme (ACE) mRNA was increased in VSMCs but decreased to 50% in HUVECs during the same apoptotic process. Increases in the expression of AGT protein and angiotensin II (Ang II) were found in a serum-free medium conditioned by HUVECs (SSC). The increased Ang II was suppressed using lisinopril (an ACE inhibitor) treatment. Moreover, the activation of ERK1/2 induced by the SSC in VSMCs was also suppressed by losartan. In conclusion, we first demonstrated that the augmented AGT released from apoptotic endothelial cells acts as a vital progenitor of Ang II to accelerate vascular remodelling, and we suggest that blocking local augmented Ang II might be an effective strategy for restraining intimal hyperplasia.

No MeSH data available.


Related in: MedlinePlus