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Published on: March 8, 2019
TRPV5 attenuates abdominal aortic aneurysm in mice by regulating KLF4-dependent phenotype switch of aortic vascular
Shuo Wang1, Xiaoxiang Tian2, Dan Liu2
1Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, China; Department of Cardiology and Cardiovascular Research Institute, General Hospital of Northern Theater Command, Shenyang, China.
Abstract:
Abdominal aortic aneurysm (AAA) is a fatal vascular disease with insidious symptoms. However, the mechanism behind its development remains unclear. The transient receptor potential vanilloid (TRPV) family has crucial protective effects against cardiovascular diseases, but the role of TRPV5 in AAA has yet to be reported. In this study, ApoE-/- mice were intraperitoneally injected with AAV-GFP or AAV-TRPV5. After 30 days, mice were further administered with angiotensin II (Ang II, 1.44 mg/kg/day) by using osmotic pumps to induce the AAA model or Saline for 28 days, (i.e., Saline + AAV-GFP, Saline + AAV-TRPV5, Ang II + AAV-GFP and Ang II + AAV-TRPV5 groups were established). Compared with the control group, the incidence of AAA and the maximal diameter of the abdominal aorta markedly decreased in Ang II + AAV-TRPV5, which was detected by vascular ultrasound at 28 day. Meanwhile, less collagen and elastin degradation were observed in the Ang II + AAV-TRPV5 group by using Masson and Elastin stains. Moreover, more α-SMA and less MMP2 was observed in the abdominal aortas collected at 28 day by immunohistochemistry. In vitro, primary mouse vascular smooth muscle cells (VSMCs) were treated with Ang II (1 μM) to induce phenotype switch. Sh-TRPV5 and AdTRPV5 were used to transfect VSMCs. PCR and Western blotting were used to access the expression of contractile marker, including α-SMA and SM-22α. The results showed that the mRNA and protein level of α-SMA and SM-22α were decreased under the stimulation of Ang II, but could be attenuated by TRPV5 overexpression. The cell scratch assay demonstrated that the migration ability of VSMCs was increased in Ang II treated group and could be ameliorated by TRPV5 overexpression. Above all, VSMCs transformed from the contractile into secretory phenotype under Ang II stimuli, but could be rescued by TRPV5 overexpression. Furthermore, TRPV5 overexpression suppressed the increased expression of KLF4 induced by Ang II treatment in VSMCs. The data demonstrated that TRPV5 could inhibit AAA formation and play a critical role in the VSMC phenotype switch by downregulating KLF4, suggesting TRPV5 as a new strategy for treating AAA.
Insights
Transient Receptor Potential Vanilloid 5 (TRPV5) protects against abdominal aortic aneurysm (AAA) by preventing vascular smooth muscle cell changes. Overexpressing TRPV5 inhibits AAA formation and offers a new therapeutic strategy.
Area of Science:
- Cardiovascular Biology
- Vascular Physiology
- Molecular Medicine
Background:
- Abdominal aortic aneurysm (AAA) is a dangerous vascular disease with unknown mechanisms.
- The Transient Receptor Potential Vanilloid (TRPV) family is vital for cardiovascular health, but TRPV5's role in AAA is unstudied.
Purpose of the Study:
- To investigate the role of TRPV5 in the development of abdominal aortic aneurysm (AAA).
- To explore TRPV5's effect on vascular smooth muscle cell (VSMC) phenotype switching in AAA.
Main Methods:
- An abdominal aortic aneurysm (AAA) mouse model was created using angiotensin II (Ang II) infusion in ApoE-/- mice, with some receiving AAV-TRPV5 gene therapy.
- Vascular ultrasound, Masson and Elastin staining, and immunohistochemistry were used to assess AAA development and aortic tissue.
- In vitro studies involved treating primary mouse vascular smooth muscle cells (VSMCs) with Ang II and transfecting them with TRPV5 vectors to analyze gene and protein expression (α-SMA, SM-22α, KLF4) and cell migration.
Main Results:
- TRPV5 overexpression significantly reduced AAA incidence and aortic diameter, with less collagen/elastin degradation and altered α-SMA and MMP2 levels.
- In vitro, TRPV5 overexpression counteracted Ang II-induced decreases in contractile markers (α-SMA, SM-22α) and VSMC migration.
- TRPV5 inhibited Ang II-induced VSMC transformation to a secretory phenotype by downregulating KLF4 expression.
Conclusions:
- TRPV5 plays a critical protective role in preventing abdominal aortic aneurysm (AAA) formation.
- TRPV5 influences vascular smooth muscle cell (VSMC) phenotype switching by modulating KLF4, suggesting it as a potential therapeutic target for AAA.
