Amphiregulin Exerts Proangiogenic Effects in Developing Murine Lungs
Interrupted lung angiogenesis is a hallmark of bronchopulmonary dysplasia (BPD); however, druggable targets that can rescue this phenotype remain elusive. Thus, our investigation focused on amphiregulin (Areg), a growth factor that mediates cellular proliferation, differentiation, migration, surviva...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-01-01
|
| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/13/1/78 |
| _version_ | 1797344701935779840 |
|---|---|
| author | Shyam Thapa Nithyapriya Shankar Amrit Kumar Shrestha Monish Civunigunta Amos S. Gaikwad Binoy Shivanna |
| author_facet | Shyam Thapa Nithyapriya Shankar Amrit Kumar Shrestha Monish Civunigunta Amos S. Gaikwad Binoy Shivanna |
| author_sort | Shyam Thapa |
| collection | DOAJ |
| description | Interrupted lung angiogenesis is a hallmark of bronchopulmonary dysplasia (BPD); however, druggable targets that can rescue this phenotype remain elusive. Thus, our investigation focused on amphiregulin (Areg), a growth factor that mediates cellular proliferation, differentiation, migration, survival, and repair. While Areg promotes lung branching morphogenesis, its effect on endothelial cell (EC) homeostasis in developing lungs is understudied. Therefore, we hypothesized that Areg promotes the proangiogenic ability of the ECs in developing murine lungs exposed to hyperoxia. Lung tissues were harvested from neonatal mice exposed to normoxia or hyperoxia to determine Areg expression. Next, we performed genetic loss-of-function and pharmacological gain-of-function studies in normoxia- and hyperoxia-exposed fetal murine lung ECs. Hyperoxia increased <i>Areg</i> mRNA levels and Areg+ cells in whole lungs. While <i>Areg</i> expression was increased in lung ECs exposed to hyperoxia, the expression of its signaling receptor, <i>epidermal growth factor receptor</i>, was decreased, indicating that hyperoxia reduces <i>Areg</i> signaling in lung ECs. <i>Areg deficiency</i> potentiated hyperoxia-mediated anti-angiogenic effects. In contrast, Areg treatment increased extracellular signal-regulated kinase activation and exerted proangiogenic effects. In conclusion, Areg promotes EC tubule formation in developing murine lungs exposed to hyperoxia. |
| first_indexed | 2024-03-08T11:06:33Z |
| format | Article |
| id | doaj.art-a43368c33842488aba3f7e69fd81e64c |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-08T11:06:33Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-a43368c33842488aba3f7e69fd81e64c2024-01-26T14:41:13ZengMDPI AGAntioxidants2076-39212024-01-011317810.3390/antiox13010078Amphiregulin Exerts Proangiogenic Effects in Developing Murine LungsShyam Thapa0Nithyapriya Shankar1Amrit Kumar Shrestha2Monish Civunigunta3Amos S. Gaikwad4Binoy Shivanna5Division of Neonatology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine (BCM), Houston, TX 77030, USAOchsner Clinical School, The University of Queensland Faculty of Medicine, 1401 Jefferson Hwy, Jefferson, LA 70121, USADivision of Neonatology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine (BCM), Houston, TX 77030, USADivision of Neonatology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine (BCM), Houston, TX 77030, USADivision of Hematology and Oncology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine (BCM), Houston, TX 77030, USADivision of Neonatology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine (BCM), Houston, TX 77030, USAInterrupted lung angiogenesis is a hallmark of bronchopulmonary dysplasia (BPD); however, druggable targets that can rescue this phenotype remain elusive. Thus, our investigation focused on amphiregulin (Areg), a growth factor that mediates cellular proliferation, differentiation, migration, survival, and repair. While Areg promotes lung branching morphogenesis, its effect on endothelial cell (EC) homeostasis in developing lungs is understudied. Therefore, we hypothesized that Areg promotes the proangiogenic ability of the ECs in developing murine lungs exposed to hyperoxia. Lung tissues were harvested from neonatal mice exposed to normoxia or hyperoxia to determine Areg expression. Next, we performed genetic loss-of-function and pharmacological gain-of-function studies in normoxia- and hyperoxia-exposed fetal murine lung ECs. Hyperoxia increased <i>Areg</i> mRNA levels and Areg+ cells in whole lungs. While <i>Areg</i> expression was increased in lung ECs exposed to hyperoxia, the expression of its signaling receptor, <i>epidermal growth factor receptor</i>, was decreased, indicating that hyperoxia reduces <i>Areg</i> signaling in lung ECs. <i>Areg deficiency</i> potentiated hyperoxia-mediated anti-angiogenic effects. In contrast, Areg treatment increased extracellular signal-regulated kinase activation and exerted proangiogenic effects. In conclusion, Areg promotes EC tubule formation in developing murine lungs exposed to hyperoxia.https://www.mdpi.com/2076-3921/13/1/78angiogenesisamphiregulinfetal murine lung endothelial cellshyperoxiabronchopulmonary dysplasia |
| spellingShingle | Shyam Thapa Nithyapriya Shankar Amrit Kumar Shrestha Monish Civunigunta Amos S. Gaikwad Binoy Shivanna Amphiregulin Exerts Proangiogenic Effects in Developing Murine Lungs Antioxidants angiogenesis amphiregulin fetal murine lung endothelial cells hyperoxia bronchopulmonary dysplasia |
| title | Amphiregulin Exerts Proangiogenic Effects in Developing Murine Lungs |
| title_full | Amphiregulin Exerts Proangiogenic Effects in Developing Murine Lungs |
| title_fullStr | Amphiregulin Exerts Proangiogenic Effects in Developing Murine Lungs |
| title_full_unstemmed | Amphiregulin Exerts Proangiogenic Effects in Developing Murine Lungs |
| title_short | Amphiregulin Exerts Proangiogenic Effects in Developing Murine Lungs |
| title_sort | amphiregulin exerts proangiogenic effects in developing murine lungs |
| topic | angiogenesis amphiregulin fetal murine lung endothelial cells hyperoxia bronchopulmonary dysplasia |
| url | https://www.mdpi.com/2076-3921/13/1/78 |
| work_keys_str_mv | AT shyamthapa amphiregulinexertsproangiogeniceffectsindevelopingmurinelungs AT nithyapriyashankar amphiregulinexertsproangiogeniceffectsindevelopingmurinelungs AT amritkumarshrestha amphiregulinexertsproangiogeniceffectsindevelopingmurinelungs AT monishcivunigunta amphiregulinexertsproangiogeniceffectsindevelopingmurinelungs AT amossgaikwad amphiregulinexertsproangiogeniceffectsindevelopingmurinelungs AT binoyshivanna amphiregulinexertsproangiogeniceffectsindevelopingmurinelungs |