Calcitonin gene-related peptide protects from soluble fms-like tyrosine kinase-1-induced vascular dysfunction in a preeclampsia mouse model
Introduction: Preeclampsia (PE) is a hypertensive disorder during pregnancy associated with elevated levels of soluble FMS-like tyrosine kinase (sFLT-1) and increased vascular sensitivity to angiotensin II (ATII). Calcitonin gene-related peptide (CALCA) is a potent vasodilator that inhibits the ATII...
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Frontiers Media S.A.
2023-08-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2023.1221684/full |
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| author | Akansha Mishra Ancizar Betancourt Vipin Alukkal Vidyadharan Chellakkan Selvanesan Blesson Michael Belfort Chandra Yallampalli Madhu Chauhan |
| author_facet | Akansha Mishra Ancizar Betancourt Vipin Alukkal Vidyadharan Chellakkan Selvanesan Blesson Michael Belfort Chandra Yallampalli Madhu Chauhan |
| author_sort | Akansha Mishra |
| collection | DOAJ |
| description | Introduction: Preeclampsia (PE) is a hypertensive disorder during pregnancy associated with elevated levels of soluble FMS-like tyrosine kinase (sFLT-1) and increased vascular sensitivity to angiotensin II (ATII). Calcitonin gene-related peptide (CALCA) is a potent vasodilator that inhibits the ATII-induced increase in blood pressure and protects against ATII-induced increases in oxidative stress through a mitochondrial-dependent pathway in male mice. In rodent pregnancy, CALCA facilitates pregnancy-induced vascular adaptation. Most of the vascular effects of CALCA are mediated by vascular smooth muscle cells (VSMCs). We recently reported that CALCA treatment inhibits sFLT-1-induced decreases in cAMP synthesis in omental artery smooth muscle cells (OASMCs) isolated from pregnant women and has relaxant effects in omental arteries (OAs) isolated from pregnant women with preeclamptic (PE) pregnancies. The current study was designed to assess the effects of sFLT-1 on mitochondrial bioenergetics in OASMCs isolated from pregnant women in the presence or absence of CALCA and assess the development of vascular dysfunction in sFLT-1 using a mouse model of PE pregnancy.Methods: OASMCs were isolated from pregnant women to assess the effects of sFLT-1 on mitochondrial bioenergetics and oxidative stress using the Seahorse assay and quantitative PCR. Pregnant mice overexpressing sFLT-1 via adenoviral delivery were used to assess the effects of CALCA infusion on the sFLT-1-induced increase in blood pressure, ATII hypersensitivity, fetal growth restriction, and the elevated albumin–creatinine ratio. Systemic blood pressure was recorded in conscious, freely moving mice using implantable radio telemetry devices.Results: CALCA inhibited the following sFLT-1-induced effects: 1) increased oxidative stress and the decreased oxygen consumption rate (OCR) in response to maximal respiration and ATP synthesis; 2) increases in the expression of mitochondrial enzyme complexes in OASMCs; 3) increased mitochondrial fragmentation in OASMCs; 4) decreased expression of mitophagy-associated PINK1 and DRAM1 mRNA expression in OASMCs; and 5) increased blood pressure, ATII hypersensitivity, fetal growth restriction, and the albumin–creatinine ratio in sFLT-1-overexpressing pregnant mice.Conclusion: CALCA inhibits sFLT-1-induced alterations in mitochondrial bioenergetics in vascular smooth muscle cells and development of maternal vascular dysfunction in a mouse model of PE. |
| first_indexed | 2024-03-12T11:49:24Z |
| format | Article |
| id | doaj.art-310f018bf4f644fab46ea667394ea138 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-03-12T11:49:24Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Physiology |
| spelling | doaj.art-310f018bf4f644fab46ea667394ea1382023-08-31T10:15:04ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2023-08-011410.3389/fphys.2023.12216841221684Calcitonin gene-related peptide protects from soluble fms-like tyrosine kinase-1-induced vascular dysfunction in a preeclampsia mouse modelAkansha MishraAncizar BetancourtVipin Alukkal VidyadharanChellakkan Selvanesan BlessonMichael BelfortChandra YallampalliMadhu ChauhanIntroduction: Preeclampsia (PE) is a hypertensive disorder during pregnancy associated with elevated levels of soluble FMS-like tyrosine kinase (sFLT-1) and increased vascular sensitivity to angiotensin II (ATII). Calcitonin gene-related peptide (CALCA) is a potent vasodilator that inhibits the ATII-induced increase in blood pressure and protects against ATII-induced increases in oxidative stress through a mitochondrial-dependent pathway in male mice. In rodent pregnancy, CALCA facilitates pregnancy-induced vascular adaptation. Most of the vascular effects of CALCA are mediated by vascular smooth muscle cells (VSMCs). We recently reported that CALCA treatment inhibits sFLT-1-induced decreases in cAMP synthesis in omental artery smooth muscle cells (OASMCs) isolated from pregnant women and has relaxant effects in omental arteries (OAs) isolated from pregnant women with preeclamptic (PE) pregnancies. The current study was designed to assess the effects of sFLT-1 on mitochondrial bioenergetics in OASMCs isolated from pregnant women in the presence or absence of CALCA and assess the development of vascular dysfunction in sFLT-1 using a mouse model of PE pregnancy.Methods: OASMCs were isolated from pregnant women to assess the effects of sFLT-1 on mitochondrial bioenergetics and oxidative stress using the Seahorse assay and quantitative PCR. Pregnant mice overexpressing sFLT-1 via adenoviral delivery were used to assess the effects of CALCA infusion on the sFLT-1-induced increase in blood pressure, ATII hypersensitivity, fetal growth restriction, and the elevated albumin–creatinine ratio. Systemic blood pressure was recorded in conscious, freely moving mice using implantable radio telemetry devices.Results: CALCA inhibited the following sFLT-1-induced effects: 1) increased oxidative stress and the decreased oxygen consumption rate (OCR) in response to maximal respiration and ATP synthesis; 2) increases in the expression of mitochondrial enzyme complexes in OASMCs; 3) increased mitochondrial fragmentation in OASMCs; 4) decreased expression of mitophagy-associated PINK1 and DRAM1 mRNA expression in OASMCs; and 5) increased blood pressure, ATII hypersensitivity, fetal growth restriction, and the albumin–creatinine ratio in sFLT-1-overexpressing pregnant mice.Conclusion: CALCA inhibits sFLT-1-induced alterations in mitochondrial bioenergetics in vascular smooth muscle cells and development of maternal vascular dysfunction in a mouse model of PE.https://www.frontiersin.org/articles/10.3389/fphys.2023.1221684/fullcalcitonin gene-related peptidesFlt-1mitochondrial functionvascular smooth muscle cellspreeclampsia |
| spellingShingle | Akansha Mishra Ancizar Betancourt Vipin Alukkal Vidyadharan Chellakkan Selvanesan Blesson Michael Belfort Chandra Yallampalli Madhu Chauhan Calcitonin gene-related peptide protects from soluble fms-like tyrosine kinase-1-induced vascular dysfunction in a preeclampsia mouse model Frontiers in Physiology calcitonin gene-related peptide sFlt-1 mitochondrial function vascular smooth muscle cells preeclampsia |
| title | Calcitonin gene-related peptide protects from soluble fms-like tyrosine kinase-1-induced vascular dysfunction in a preeclampsia mouse model |
| title_full | Calcitonin gene-related peptide protects from soluble fms-like tyrosine kinase-1-induced vascular dysfunction in a preeclampsia mouse model |
| title_fullStr | Calcitonin gene-related peptide protects from soluble fms-like tyrosine kinase-1-induced vascular dysfunction in a preeclampsia mouse model |
| title_full_unstemmed | Calcitonin gene-related peptide protects from soluble fms-like tyrosine kinase-1-induced vascular dysfunction in a preeclampsia mouse model |
| title_short | Calcitonin gene-related peptide protects from soluble fms-like tyrosine kinase-1-induced vascular dysfunction in a preeclampsia mouse model |
| title_sort | calcitonin gene related peptide protects from soluble fms like tyrosine kinase 1 induced vascular dysfunction in a preeclampsia mouse model |
| topic | calcitonin gene-related peptide sFlt-1 mitochondrial function vascular smooth muscle cells preeclampsia |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2023.1221684/full |
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