Beneficial effects of platelet-derived growth factor on hemorrhagic shock in rats and the underlying mechanisms

Studies have shown that local application of platelet-derived growth factor (PDGF) can be used for the treatment of acute and chronic wounds. We investigated if systemic application of PDGF has a protective effect on acute hemorrhagic shock in rats in the present study. Using hemorrhagic shock rats and isolated superior mesenteric arteries, the effects of PDGF-BB on hemodynamics, animal survival, and vascular reactivity as well as the roles of the gap junction proteins connexin (Cx)40 and Cx43, PKC, and Rho kinase were observed. PDGF-BB (1–15 μg/kg iv) significantly improved the hemodynamics and blood perfusion to vital organs (liver and kidney) as well as vascular reactivity and improved the animal survival in hemorrhagic shock rats. PDGF recovering shock-induced vascular hyporeactivity depended on the integrity of the endothelium and myoendothelial gap junction. Cx43 antisense oligodeoxynucleotide abolished these improving effects of PDGF, whereas Cx40 oligodeoxynucleotide did not. Further study indicated that PDGF increased the activity of Rho kinase and PKC as well as vascular Ca2+sensitivity, whereas it did not interfere with the intracellular Ca2+concentration in hypoxia-treated vascular smooth muscle cells. In conclusion, systemic application of PDGF-BB may exert beneficial effects on hemorrhagic shock, which are closely related to the improvement of vascular reactivity and hemodynamics. The improvement of PDGF-BB in vascular reactivity is vascular endothelium and myoendothelial gap junction dependent. Cx43, Rho kinase, and PKC play very important role in this process. These findings suggest that PDGF may be a potential measure to treat acute clinical critical diseases such as severe trauma, shock, and sepsis.

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The mechanism by which RhoA regulates vascular reactivity after hemorrhagic shock in rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01031.2009 ◽

2010 ◽

Vol 299 (2) ◽

pp. H292-H299 ◽

Cited By ~ 17

Author(s):

Tao Li ◽

Yuqiang Fang ◽

Guangming Yang ◽

Yu Zhu ◽

Jing Xu ◽

...

Keyword(s):

Hemorrhagic Shock ◽

Signaling Pathway ◽

Light Chain ◽

Myosin Light Chain ◽

Vascular Reactivity ◽

Kinase Inhibitor ◽

Rho Kinase ◽

Antagonistic Effect ◽

Mesenteric Arteries ◽

Signal Pathways

RhoA, an important member of the Rho family of GTPases, has been implicated in many cellular processes. Our pilot study found that RhoA participated in the regulation of vascular reactivity after shock, but the mechanism was incompletely understood. Whether RhoA regulates vascular reactivity through the Rho kinase-myosin light-chain phosphatase (MLCP) and Rac1-p21-activated kinase (PAK)-myosin light-chain kinase (MLCK) signaling pathway needs investigation. With isolated, superior mesenteric arteries from hemorrhagic-shock rats and hypoxia-treated vascular smooth muscle cells (VSMCs), the effects of U-46619 (RhoA agonist) and C3 transferase (RhoA antagonist) on vascular reactivity, and the relationship to the Rho kinase-MLCP and Rac1-PAK-MLCK signaling pathways were observed. The vascular reactivity of the superior mesenteric artery and the contractile response of VSMCs to norepinephrine after prolonged hemorrhagic shock and hypoxia (2 h) were significantly decreased. Activation of RhoA with U-46619 significantly increased shock or hypoxia-induced decreased vascular reactivity. These effects of U-46619 were abolished by Y-27632 (Rho kinase inhibitor) and PDGF (Rac1 stimulator). Y-27632 had a stronger antagonistic effect than PDGF. U-46619 increased the activity of Rho kinase and MLCK, enhanced the phosphorylation of 20-kDa myosin light chain, and decreased the activity of Rac1, PAK, and MLCP in VSMCs after hypoxia. Y-27632-antagonized U-46619 induced the decrease of MLCP activity and the increase of 20-kDa myosin light chain phosphorylation. PDGF-antagonized U-46619 induced decrease of PAK activity and increase of MLCK activity. RhoA has an important role in the regulation of vascular reactivity after hemorrhagic shock. The Rho kinase-MLCP and Rac1-PAK-MLCK signal pathways participate in the regulatory process of RhoA. Rho kinase-MLCP may be the main signaling pathway by which RhoA regulates vascular reactivity.

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Effect of platelet-derived growth factor-BB on gap junction and connexin43 in rat penile corpus cavernosum smooth muscle cells

Andrologia ◽

10.1111/and.13200 ◽

2018 ◽

Vol 51 (3) ◽

pp. e13200 ◽

Cited By ~ 1

Author(s):

Fan Zhao ◽

Junfeng Yan ◽

Jianfeng Zhao ◽

Bing Shi ◽

Miaoyong Ye ◽

...

Keyword(s):

Smooth Muscle ◽

Growth Factor ◽

Smooth Muscle Cells ◽

Gap Junction ◽

Corpus Cavernosum ◽

Muscle Cells ◽

Platelet Derived Growth Factor

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The calcilytic drug Calhex-231 ameliorates vascular hyporesponsiveness in traumatic hemorrhagic shock by inhibiting oxidative stress and mitochondrial fission

10.21203/rs.2.23868/v1 ◽

2020 ◽

Author(s):

Yan Lei ◽

Xiaoyong Peng ◽

Tao Li ◽

Liangming Liu ◽

Guangming Yang

Keyword(s):

Oxidative Stress ◽

Hemorrhagic Shock ◽

Vascular Reactivity ◽

Mitochondrial Fission ◽

Blood Perfusion ◽

Mitochondrial Fusion ◽

Vital Organ ◽

Animal Survival ◽

Traumatic Hemorrhagic Shock ◽

Mlc Phosphorylation

Abstract Background The calcium-sensing receptor (CaSR) plays a fundamental role in extracellular calcium homeostasis in humans. Surprisingly, CaSR is also expressed in non-homeostatic tissues and is involved in regulating diverse cellular functions. The objective of this study was to determine if Calhex-231 (Cal), a negative modulator of CaSR, may be beneficial in the treatment of traumatic hemorrhagic shock (THS) by improving cardiovascular function, and investigated its relationship to oxidative stress and the mitochondrial fusion-fission pathway. Methods Rats that had been subjected to traumatic hemorrhagic shock were used as models in this study. Hypoxia-treated vascular smooth muscle cells (VSMCs) were also used. The effects of Cal on cardiovascular function, animal survival, hemodynamic parameters, and vital organ function in THS rats were observed, and the relationship to oxidative stress and mitochondrial fusion-fission was investigated. Results Cal significantly improved hemodynamics, elevated blood pressure, increased vital organ blood perfusion and local oxygen supply, and markedly improved the survival outcomes of THS rats. Furthermore, Cal significantly improved vascular reactivity after THS, including the pressor response of THS rats to norepinephrine (NE), and also the contractile response of superior mesenteric arteries, mesenteric arterioles, and isolated VSMCs to NE. Cal also restored the THS-induced decrease in myosin light chain (MLC) phosphorylation, which is the principal mechanism responsible for VSMC contraction and vascular reactivity. Inhibition of MLC phosphorylation antagonized the Cal-induced restoration of vascular reactivity following THS. Cal decreased oxidative stress indexes and increased antioxidant enzyme levels in THS rats, and also reduced reactive oxygen species levels in hypoxic VSMCs. In addition, THS induced expression of mitochondrial fission proteins Drp1 and Fis1, and decreased expression of mitochondrial fusion protein Mfn1 in vascular tissues. Cal reduced expression of Drp1 and Fis1, but did not affect Mfn1 expression. In hypoxic VSMCs, Cal inhibited hypoxia-induced mitochondrial fragmentation and preserved mitochondrial morphology. Conclusions Calhex-231 exhibits outstanding potential for effective therapy of traumatic hemorrhagic shock, due to its ability to improve hemodynamics, increase vital organ blood perfusion, and markedly prolong animal survival. These beneficial effects result from its protection of vascular function via inhibition of oxidative stress and mitochondrial fission.

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