Advantages in Wound Healing Process in Female Mice Require Upregulation A2A-Mediated Angiogenesis under the Stimulation of 17β-Estradiol

Troncoso, Felipe; Herlitz, Kurt; Acurio, Jesenia; Aguayo, Claudio; Guevara, Katherine; Castro, Fidel Ovídio; Godoy, Alejandro; Martín, Sebastián San; Escudero, Carlos

doi:10.3390/ijms21197145

Cited by 13 publications

(12 citation statements)

References 35 publications

(61 reference statements)

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“…Adenosine receptors A2a and A2b are prevalent on endothelial cells and mediate the adenosine response to injury through cAMP/MAPK/ERK pathway signaling [ 29 ]. These receptors are specifically regulated by both hypoxia and estrogen, however, crosstalk between adenosine generation and estrogen remains poorly understood [ 30 , 31 , 32 ]. Our data demonstrate the reduction in adenosine with the inhibition of estrogen receptors and conversely, with estradiol exposure, decreased extracellular ATP.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Hypoxic–Adenosinergic Signaling by Estrogen: Implications for Microvascular Injury

et al. 2023

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Loss of estrogen, as occurs with normal aging, leads to increased inflammation, pathologic angiogenesis, impaired mitochondrial function, and microvascular disease. While the influence of estrogens on purinergic pathways is largely unknown, extracellular adenosine, generated at high levels by CD39 and CD73, is known to be anti-inflammatory in the vasculature. To further define the cellular mechanisms necessary for vascular protection, we investigated how estrogen modulates hypoxic–adenosinergic vascular signaling responses and angiogenesis. Expression of estrogen receptors, purinergic mediators inclusive of adenosine, adenosine deaminase (ADA), and ATP were measured in human endothelial cells. Standard tube formation and wound healing assays were performed to assess angiogenesis in vitro. The impacts on purinergic responses in vivo were modeled using cardiac tissue from ovariectomized mice. CD39 and estrogen receptor alpha (ERα) levels were markedly increased in presence of estradiol (E2). Suppression of ERα resulted in decreased CD39 expression. Expression of ENT1 was decreased in an ER-dependent manner. Extracellular ATP and ADA activity levels decreased following E2 exposure while levels of adenosine increased. Phosphorylation of ERK1/2 increased following E2 treatment and was attenuated by blocking adenosine receptor (AR) and ER activity. Estradiol boosted angiogenesis, while inhibition of estrogen decreased tube formation in vitro. Expression of CD39 and phospho-ERK1/2 decreased in cardiac tissues from ovariectomized mice, whereas ENT1 expression increased with expected decreases in blood adenosine levels. Estradiol-induced upregulation of CD39 substantially increases adenosine availability, while augmenting vascular protective signaling responses. Control of CD39 by ERα follows on transcriptional regulation. These data suggest novel therapeutic avenues to explore in the amelioration of post-menopausal cardiovascular disease, by modulation of adenosinergic mechanisms.

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Section: Discussionmentioning

confidence: 99%

Regulation of Hypoxic–Adenosinergic Signaling by Estrogen: Implications for Microvascular Injury

et al. 2023

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“…Pups were sexed by visual evaluation and confirmed by PCR using the expression of the jarid gene, as previously described. 28 Then, the weight-for-length ratio and weight-for-weight ratio of the brain were calculated individually. After that, brains were collected in 300 ml of RIPA buffer and frozen at À20 C until further analysis.…”

Section: Offspring Morphometry and Measurementsmentioning

confidence: 99%

Abnormal cerebral microvascular perfusion and reactivity in female offspring of reduced uterine perfusion pressure (RUPP) mice model

Lara

Rivera

González-Bernal

et al. 2022

J Cereb Blood Flow Metab

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Children born from women with preeclampsia have alterations in cerebral neurovascular development and a high risk for developing cognitive alterations. Because cerebral blood vessels are critical components in cerebrovascular development, we evaluated the brain microvascular perfusion and microvascular reactivity (exposed to external stimuli of warm and cold) in pups born to preeclampsia-like syndrome based on the reduction of uterine perfusion (RUPP). Also, we evaluate the angiogenic proteomic profile in those brains. Pregnant mice showed a reduction in uterine flow after RUPP surgery (−40 to 50%) associated with unfavorable perinatal results compared to sham mice. Furthermore, offspring of the RUPP mice exhibited reduced brain microvascular perfusion at postnatal day 5 (P5) compared with offspring from sham mice. This reduction was preferentially observed in females. Also, brain microvascular reactivity to external stimuli (warm and cold) was reduced in pups of RUPP mice. Furthermore, a differential expression of the angiogenic profile associated with inflammation, extrinsic apoptotic, cancer, and cellular senescence processes as the primary signaling impaired process was found in the brains of RUPP-offspring. Then, offspring (P5) from preeclampsia-like syndrome exhibit impaired brain perfusion and microvascular reactivity, particularly in female mice, associated with differential expression of angiogenic proteins in the brain tissue.

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“…The in vivo wound-healing assay was performed as previously described by our laboratory [ 36 , 37 ], with slight modifications. Briefly, WT and Thy-1 −/− male mice were maintained separately in individual cages.…”

Section: Methodsmentioning

confidence: 99%

The GPI-Anchored Protein Thy-1/CD90 Promotes Wound Healing upon Injury to the Skin by Enhancing Skin Perfusion

Pérez

León

López

et al. 2022

IJMS

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Wound healing is a highly regulated multi-step process that involves a plethora of signals. Blood perfusion is crucial in wound healing and abnormalities in the formation of new blood vessels define the outcome of the wound healing process. Thy-1 has been implicated in angiogenesis and silencing of the Thy-1 gene retards the wound healing process. However, the role of Thy-1 in blood perfusion during wound closure remains unclear. We proposed that Thy-1 regulates vascular perfusion, affecting the healing rate in mouse skin. We analyzed the time of recovery, blood perfusion using Laser Speckle Contrast Imaging, and tissue morphology from images acquired with a Nanozoomer tissue scanner. The latter was assessed in a tissue sample taken with a biopsy punch on several days during the wound healing process. Results obtained with the Thy-1 knockout (Thy-1−/−) mice were compared with control mice. Thy-1−/− mice showed at day seven, a delayed re-epithelialization, increased micro- to macro-circulation ratio, and lower blood perfusion in the wound area. In addition, skin morphology displayed a flatter epidermis, fewer ridges, and almost no stratum granulosum or corneum, while the dermis was thicker, showing more fibroblasts and fewer lymphocytes. Our results suggest a critical role for Thy-1 in wound healing, particularly in vascular dynamics.

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Advantages in Wound Healing Process in Female Mice Require Upregulation A2A-Mediated Angiogenesis under the Stimulation of 17β-Estradiol

Cited by 13 publications

References 35 publications

Regulation of Hypoxic–Adenosinergic Signaling by Estrogen: Implications for Microvascular Injury

Regulation of Hypoxic–Adenosinergic Signaling by Estrogen: Implications for Microvascular Injury

Abnormal cerebral microvascular perfusion and reactivity in female offspring of reduced uterine perfusion pressure (RUPP) mice model

The GPI-Anchored Protein Thy-1/CD90 Promotes Wound Healing upon Injury to the Skin by Enhancing Skin Perfusion

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