HIV antiretroviral exposure in pregnancy induces detrimental placenta vascular changes that are rescued by progesterone supplementation
Abstract Adverse birth outcomes are common in HIV-positive pregnant women receiving combination antiretroviral therapy (cART), especially when cART is initiated in early pregnancy. The mechanisms remain poorly understood. Using a mouse model we demonstrate that protease inhibitor based-cART exposure...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2018-04-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-018-24680-w |
| _version_ | 1818998864567336960 |
|---|---|
| author | Hakimeh Mohammadi Eszter Papp Lindsay Cahill Monique Rennie Nicole Banko Lakmini Pinnaduwage Janice Lee Mark Kibschull Caroline Dunk John G. Sled Lena Serghides |
| author_facet | Hakimeh Mohammadi Eszter Papp Lindsay Cahill Monique Rennie Nicole Banko Lakmini Pinnaduwage Janice Lee Mark Kibschull Caroline Dunk John G. Sled Lena Serghides |
| author_sort | Hakimeh Mohammadi |
| collection | DOAJ |
| description | Abstract Adverse birth outcomes are common in HIV-positive pregnant women receiving combination antiretroviral therapy (cART), especially when cART is initiated in early pregnancy. The mechanisms remain poorly understood. Using a mouse model we demonstrate that protease inhibitor based-cART exposure beginning on day 1 of pregnancy was associated with a pro-angiogenic/pro-branching shift in the placenta driven by lower Flt-1 levels and higher Gcm-1 expression. Micro-CT imaging revealed an increase in the number of arterioles in cART-treated placentas, which correlated with fetal growth restriction. Delaying initiation of cART, or supplementing cART-treated mice with progesterone, prevented the pro-angiogenic/pro-branching shift and the associated placenta vascular changes. In agreement with our mouse findings, we observed an increase in the number of terminal-villi capillaries in placentas from HIV-positive cART-exposed women compared to HIV-negative controls. Capillary number was inversely correlated to maternal progesterone levels. Our study provides evidence that cART exposure during pregnancy influences placenta vascular formation that may in turn contribute to fetal growth restriction. Our findings highlight the need for closer investigation of the placenta in HIV-positive pregnancies, particularly for pregnancies exposed to cART from conception, and suggest that progesterone supplementation could be investigated as a possible intervention to improve placenta function in HIV-positive pregnant women. |
| first_indexed | 2024-12-20T22:08:18Z |
| format | Article |
| id | doaj.art-37bf226f60dd4bb08d817725f3d25913 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-20T22:08:18Z |
| publishDate | 2018-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-37bf226f60dd4bb08d817725f3d259132022-12-21T19:25:13ZengNature PortfolioScientific Reports2045-23222018-04-018111410.1038/s41598-018-24680-wHIV antiretroviral exposure in pregnancy induces detrimental placenta vascular changes that are rescued by progesterone supplementationHakimeh Mohammadi0Eszter Papp1Lindsay Cahill2Monique Rennie3Nicole Banko4Lakmini Pinnaduwage5Janice Lee6Mark Kibschull7Caroline Dunk8John G. Sled9Lena Serghides10Toronto General Hospital Research Institute, University Health NetworkToronto General Hospital Research Institute, University Health NetworkMouse Imaging Centre, The Hospital for Sick ChildrenMouse Imaging Centre, The Hospital for Sick ChildrenToronto General Hospital Research Institute, University Health NetworkResearch Centre for Women’s and Infants’ Health, Lunenfeld Tanenbaum Research Institute, Mount Sinai HospitalToronto General Hospital Research Institute, University Health NetworkResearch Centre for Women’s and Infants’ Health, Lunenfeld Tanenbaum Research Institute, Mount Sinai HospitalResearch Centre for Women’s and Infants’ Health, Lunenfeld Tanenbaum Research Institute, Mount Sinai HospitalMouse Imaging Centre, The Hospital for Sick ChildrenToronto General Hospital Research Institute, University Health NetworkAbstract Adverse birth outcomes are common in HIV-positive pregnant women receiving combination antiretroviral therapy (cART), especially when cART is initiated in early pregnancy. The mechanisms remain poorly understood. Using a mouse model we demonstrate that protease inhibitor based-cART exposure beginning on day 1 of pregnancy was associated with a pro-angiogenic/pro-branching shift in the placenta driven by lower Flt-1 levels and higher Gcm-1 expression. Micro-CT imaging revealed an increase in the number of arterioles in cART-treated placentas, which correlated with fetal growth restriction. Delaying initiation of cART, or supplementing cART-treated mice with progesterone, prevented the pro-angiogenic/pro-branching shift and the associated placenta vascular changes. In agreement with our mouse findings, we observed an increase in the number of terminal-villi capillaries in placentas from HIV-positive cART-exposed women compared to HIV-negative controls. Capillary number was inversely correlated to maternal progesterone levels. Our study provides evidence that cART exposure during pregnancy influences placenta vascular formation that may in turn contribute to fetal growth restriction. Our findings highlight the need for closer investigation of the placenta in HIV-positive pregnancies, particularly for pregnancies exposed to cART from conception, and suggest that progesterone supplementation could be investigated as a possible intervention to improve placenta function in HIV-positive pregnant women.https://doi.org/10.1038/s41598-018-24680-w |
| spellingShingle | Hakimeh Mohammadi Eszter Papp Lindsay Cahill Monique Rennie Nicole Banko Lakmini Pinnaduwage Janice Lee Mark Kibschull Caroline Dunk John G. Sled Lena Serghides HIV antiretroviral exposure in pregnancy induces detrimental placenta vascular changes that are rescued by progesterone supplementation Scientific Reports |
| title | HIV antiretroviral exposure in pregnancy induces detrimental placenta vascular changes that are rescued by progesterone supplementation |
| title_full | HIV antiretroviral exposure in pregnancy induces detrimental placenta vascular changes that are rescued by progesterone supplementation |
| title_fullStr | HIV antiretroviral exposure in pregnancy induces detrimental placenta vascular changes that are rescued by progesterone supplementation |
| title_full_unstemmed | HIV antiretroviral exposure in pregnancy induces detrimental placenta vascular changes that are rescued by progesterone supplementation |
| title_short | HIV antiretroviral exposure in pregnancy induces detrimental placenta vascular changes that are rescued by progesterone supplementation |
| title_sort | hiv antiretroviral exposure in pregnancy induces detrimental placenta vascular changes that are rescued by progesterone supplementation |
| url | https://doi.org/10.1038/s41598-018-24680-w |
| work_keys_str_mv | AT hakimehmohammadi hivantiretroviralexposureinpregnancyinducesdetrimentalplacentavascularchangesthatarerescuedbyprogesteronesupplementation AT eszterpapp hivantiretroviralexposureinpregnancyinducesdetrimentalplacentavascularchangesthatarerescuedbyprogesteronesupplementation AT lindsaycahill hivantiretroviralexposureinpregnancyinducesdetrimentalplacentavascularchangesthatarerescuedbyprogesteronesupplementation AT moniquerennie hivantiretroviralexposureinpregnancyinducesdetrimentalplacentavascularchangesthatarerescuedbyprogesteronesupplementation AT nicolebanko hivantiretroviralexposureinpregnancyinducesdetrimentalplacentavascularchangesthatarerescuedbyprogesteronesupplementation AT lakminipinnaduwage hivantiretroviralexposureinpregnancyinducesdetrimentalplacentavascularchangesthatarerescuedbyprogesteronesupplementation AT janicelee hivantiretroviralexposureinpregnancyinducesdetrimentalplacentavascularchangesthatarerescuedbyprogesteronesupplementation AT markkibschull hivantiretroviralexposureinpregnancyinducesdetrimentalplacentavascularchangesthatarerescuedbyprogesteronesupplementation AT carolinedunk hivantiretroviralexposureinpregnancyinducesdetrimentalplacentavascularchangesthatarerescuedbyprogesteronesupplementation AT johngsled hivantiretroviralexposureinpregnancyinducesdetrimentalplacentavascularchangesthatarerescuedbyprogesteronesupplementation AT lenaserghides hivantiretroviralexposureinpregnancyinducesdetrimentalplacentavascularchangesthatarerescuedbyprogesteronesupplementation |