Estradiol Downregulates MicroRNA-193a to Mediate Its Angiogenic Actions
Estrogens regulate many physiological processes in the human body, including the cardiovascular system. Importantly, Estradiol (E2) exerts its vascular protective actions, in part, by promoting endothelial repair via induction of endothelial cell (EC) proliferation, migration and angiogenesis. Recen...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-07-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/14/15/1134 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849407484166406144 |
|---|---|
| author | Lisa Rigassi Mirel Adrian Popa Ruth Stiller Brigitte Leeners Marinella Rosselli Raghvendra Krishna Dubey |
| author_facet | Lisa Rigassi Mirel Adrian Popa Ruth Stiller Brigitte Leeners Marinella Rosselli Raghvendra Krishna Dubey |
| author_sort | Lisa Rigassi |
| collection | DOAJ |
| description | Estrogens regulate many physiological processes in the human body, including the cardiovascular system. Importantly, Estradiol (E2) exerts its vascular protective actions, in part, by promoting endothelial repair via induction of endothelial cell (EC) proliferation, migration and angiogenesis. Recent evidence that microRNAs (miRNAs) play an important role in vascular health and disease as well as in regulating Estrogen actions in many cell types. We hypothesize that E2 may mediate its vascular protective actions via the regulation of miRNAs. Following initial screening, we found that E2 downregulates the levels of miR-193a-3p in ECs. Moreover, miR-193a-3p downregulation by miR-193a-3p-antimir mimicked the effects as E2 on EC growth, migration, and capillary formation. Restoring miR-193a-3p levels with mimics after E2 treatment abrogated the vasculogenic actions of E2, suggesting a key role of miR-193a-3p in E2-mediated EC-growth-promoting effects. We further investigated the cellular mechanisms involved and found that miR-193a-3p inhibits angiogenesis by blocking phosphoinositide-3-kinase (PI3K)/Akt-vascular endothelial growth factor (VEGF) and Activin receptor-like kinase 1 (ALK1)/SMAD1/5/8 signaling in ECs, both pathways that are important in E2-mediated vascular protection. Additionally, using reverse transcription polymerase chain reaction (RT-PCR), we demonstrate that E2 downregulates miR-193a-3p in ECs via Estrogen Receptor (ER)α, but not ERβ or G protein-coupled estrogen receptor (GPER). Moreover, these actions occur post-transcriptionally, as the expression of pri-miR-193a-3p was not affected. The anti-angiogenic actions of miR-193a-3p were also observed in in vivo Matrigel implant-based capillary formation studies in ovariectomized mice where E2 induced capillary formation, and these effects were abrogated in the presence of miR-193a-3p, but not in the control mimic. Assessment of miR-193a-3p levels in plasma collected from in vitro fertilization (IVF) subjects with low and high E2 levels showed significantly lower miR-193a-3p levels in responders during the high E2 period. Hence, our findings provide the first evidence that miR-193a-3p mimic inhibits angiogenesis whereas its antimir is angiogenic. Importantly, E2 mediates its regenerative actions on ECs/capillary formation by downregulating endogenous miR-193a-3p expression. Both miR-193a-3p mimic or antimir may represent important therapeutic molecules to prevent or to induce endothelial function in treating pathophysiologies associated with capillary growth. |
| format | Article |
| id | doaj-art-07c4c7a8126e41e9baf0cc6b0005e9e8 |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj-art-07c4c7a8126e41e9baf0cc6b0005e9e82025-08-20T03:36:03ZengMDPI AGCells2073-44092025-07-011415113410.3390/cells14151134Estradiol Downregulates MicroRNA-193a to Mediate Its Angiogenic ActionsLisa Rigassi0Mirel Adrian Popa1Ruth Stiller2Brigitte Leeners3Marinella Rosselli4Raghvendra Krishna Dubey5Department of Reproductive Endocrinology, University Hospital Zurich, 8952 Schlieren, SwitzerlandInstitute of Cellular Biology and Pathology Nicolae Simionescu, Romanian Academy, 050568 Bucharest, RomaniaDepartment of Reproductive Endocrinology, University Hospital Zurich, 8952 Schlieren, SwitzerlandDepartment of Reproductive Endocrinology, University Hospital Zurich, 8952 Schlieren, SwitzerlandDepartment of Reproductive Endocrinology, University Hospital Zurich, 8952 Schlieren, SwitzerlandDepartment of Reproductive Endocrinology, University Hospital Zurich, 8952 Schlieren, SwitzerlandEstrogens regulate many physiological processes in the human body, including the cardiovascular system. Importantly, Estradiol (E2) exerts its vascular protective actions, in part, by promoting endothelial repair via induction of endothelial cell (EC) proliferation, migration and angiogenesis. Recent evidence that microRNAs (miRNAs) play an important role in vascular health and disease as well as in regulating Estrogen actions in many cell types. We hypothesize that E2 may mediate its vascular protective actions via the regulation of miRNAs. Following initial screening, we found that E2 downregulates the levels of miR-193a-3p in ECs. Moreover, miR-193a-3p downregulation by miR-193a-3p-antimir mimicked the effects as E2 on EC growth, migration, and capillary formation. Restoring miR-193a-3p levels with mimics after E2 treatment abrogated the vasculogenic actions of E2, suggesting a key role of miR-193a-3p in E2-mediated EC-growth-promoting effects. We further investigated the cellular mechanisms involved and found that miR-193a-3p inhibits angiogenesis by blocking phosphoinositide-3-kinase (PI3K)/Akt-vascular endothelial growth factor (VEGF) and Activin receptor-like kinase 1 (ALK1)/SMAD1/5/8 signaling in ECs, both pathways that are important in E2-mediated vascular protection. Additionally, using reverse transcription polymerase chain reaction (RT-PCR), we demonstrate that E2 downregulates miR-193a-3p in ECs via Estrogen Receptor (ER)α, but not ERβ or G protein-coupled estrogen receptor (GPER). Moreover, these actions occur post-transcriptionally, as the expression of pri-miR-193a-3p was not affected. The anti-angiogenic actions of miR-193a-3p were also observed in in vivo Matrigel implant-based capillary formation studies in ovariectomized mice where E2 induced capillary formation, and these effects were abrogated in the presence of miR-193a-3p, but not in the control mimic. Assessment of miR-193a-3p levels in plasma collected from in vitro fertilization (IVF) subjects with low and high E2 levels showed significantly lower miR-193a-3p levels in responders during the high E2 period. Hence, our findings provide the first evidence that miR-193a-3p mimic inhibits angiogenesis whereas its antimir is angiogenic. Importantly, E2 mediates its regenerative actions on ECs/capillary formation by downregulating endogenous miR-193a-3p expression. Both miR-193a-3p mimic or antimir may represent important therapeutic molecules to prevent or to induce endothelial function in treating pathophysiologies associated with capillary growth.https://www.mdpi.com/2073-4409/14/15/1134estradiolmiRNA-139aendothelial cellsangiogenesiscardiovascular disorders |
| spellingShingle | Lisa Rigassi Mirel Adrian Popa Ruth Stiller Brigitte Leeners Marinella Rosselli Raghvendra Krishna Dubey Estradiol Downregulates MicroRNA-193a to Mediate Its Angiogenic Actions Cells estradiol miRNA-139a endothelial cells angiogenesis cardiovascular disorders |
| title | Estradiol Downregulates MicroRNA-193a to Mediate Its Angiogenic Actions |
| title_full | Estradiol Downregulates MicroRNA-193a to Mediate Its Angiogenic Actions |
| title_fullStr | Estradiol Downregulates MicroRNA-193a to Mediate Its Angiogenic Actions |
| title_full_unstemmed | Estradiol Downregulates MicroRNA-193a to Mediate Its Angiogenic Actions |
| title_short | Estradiol Downregulates MicroRNA-193a to Mediate Its Angiogenic Actions |
| title_sort | estradiol downregulates microrna 193a to mediate its angiogenic actions |
| topic | estradiol miRNA-139a endothelial cells angiogenesis cardiovascular disorders |
| url | https://www.mdpi.com/2073-4409/14/15/1134 |
| work_keys_str_mv | AT lisarigassi estradioldownregulatesmicrorna193atomediateitsangiogenicactions AT mireladrianpopa estradioldownregulatesmicrorna193atomediateitsangiogenicactions AT ruthstiller estradioldownregulatesmicrorna193atomediateitsangiogenicactions AT brigitteleeners estradioldownregulatesmicrorna193atomediateitsangiogenicactions AT marinellarosselli estradioldownregulatesmicrorna193atomediateitsangiogenicactions AT raghvendrakrishnadubey estradioldownregulatesmicrorna193atomediateitsangiogenicactions |