A Systematic Review on the Role of Adrenergic Receptors in Angiogenesis Regulation in Health and Disease

Xanthopoulos, Athanasios; Daskalopoulou, Iliana; Frountzi, Sofia; Papadimitriou, Evangelia

doi:10.3390/ijtm1030021

Cited by 7 publications

(5 citation statements)

References 77 publications

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“…Although our study focused primarily on periosteal cells, we also found that NE-ADRB2 signaling increased Vegfa expression in osteoblasts. Thus, it is likely that increased NE signaling induces the production of angiogenic factors not only in periosteal cells but also in other cell types during bone repair, because ADRB2 has been repeatedly shown to be a positive regulator of angiogenesis in many organ systems ( 52 ). For example, NE dose- and time-dependently induces Vegfa transcription in brown adipocytes, which is reversible by the β-blocker propranolol ( 53 , 54 ).…”

Section: Discussionmentioning

confidence: 99%

Increased β ₂ -adrenergic signaling promotes fracture healing through callus neovascularization in mice

Jahn,

Knapstein,

Otto

et al. 2024

Sci. Transl. Med.

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Traumatic brain injury (TBI) leads to skeletal changes, including bone loss in the unfractured skeleton, and paradoxically accelerates healing of bone fractures; however, the mechanisms remain unclear. TBI is associated with a hyperadrenergic state characterized by increased norepinephrine release. Here, we identified the β 2 -adrenergic receptor (ADRB2) as a mediator of skeletal changes in response to increased norepinephrine. In a murine model of femoral osteotomy combined with cortical impact brain injury, TBI was associated with ADRB2-dependent enhanced fracture healing compared with osteotomy alone. In the unfractured 12-week-old mouse skeleton, ADRB2 was required for TBI-induced decrease in bone formation and increased bone resorption. Adult 30-week-old mice had higher bone concentrations of norepinephrine, and ADRB2 expression was associated with decreased bone volume in the unfractured skeleton and better fracture healing in the injured skeleton. Norepinephrine stimulated expression of vascular endothelial growth factor A and calcitonin gene–related peptide-α (αCGRP) in periosteal cells through ADRB2, promoting formation of osteogenic type-H vessels in the fracture callus. Both ADRB2 and αCGRP were required for the beneficial effect of TBI on bone repair. Adult mice deficient in ADRB2 without TBI developed fracture nonunion despite high bone formation in uninjured bone. Blocking ADRB2 with propranolol impaired fracture healing in mice, whereas the ADRB2 agonist formoterol promoted fracture healing by regulating callus neovascularization. A retrospective cohort analysis of 72 patients with long bone fractures indicated improved callus formation in 36 patients treated with intravenous norepinephrine. These findings suggest that ADRB2 is a potential therapeutic target for promoting bone healing.

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Section: Discussionmentioning

confidence: 99%

Increased β ₂ -adrenergic signaling promotes fracture healing through callus neovascularization in mice

Jahn,

Knapstein,

Otto

et al. 2024

Sci. Transl. Med.

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“…Given that both physical activity and psychological stress are mediated by β2adrenergic receptor signaling, it is apparent that the two have interplay with one another in modulating sympathetic and parasympathetic responses. This is especially apparent with the increase in vascular endothelial growth factor, TNF-α concentration, as well as proin ammatory cytokines and interleukins, which aid in forming the optimal tumor microenvironment [70].…”

Section: Discussionmentioning

confidence: 99%

Physical and Psychological Stressors Increase Breast Tumor Growth but Differentially Alter Tumor Immunity

Dees,

Kabir,

Bahani

et al. 2024

Preprint

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Background:Triple-negative breast cancer constitutes approximately 15-20% of breast cancers and continues to be challenging to treat despite significant therapeutic advances. Epidemiological evidence suggests psychological stress correlates with decreased survival rates, while physical activity is presumed to improve survival rates of breast cancer patients. These correlations lead us to inquire whether aerobic exercise could improve cancer outcomes despite the psychological stress associated with a cancer diagnosis. In part, these parallels may be mediated by alterations in the anti-tumor immune responses meditated by neuroendocrine changes experienced during stress, which are believed to affect cancer progression. To address this, we used a syngenetic mouse model of breast cancer to study the impact of stressors. Objective: This study investigated the effects of psychological stress and/or physical activity on tumor growth and cancer immunity in mice with murine triple-negative breast cancer. Methods: We used female BALB/c mice subcutaneously injected with murine EMT6 breast carcinoma cells. Mice were assigned to treatment groups: moderate aerobic exercise, unpredictable chronic mild stress, a combination of exercise and chronic stress, or no physical/psychological stressor. Results: Mice were assessed for tumor growth and immunological changes within the primary tumors. Our studies showed both aerobic exercise and chronic mild stress resulted in larger tumors, while non-stressed/non-exercised controls had consistently smaller tumors. We found the smaller tumors exhibited higher presence of T helper and cytotoxic T cells. Additionally, we demonstrated that exercise improves the proliferative and suppressive functions of T helper and T regulatory cells, respectively, whether with or without chronic stress. Interestingly, the anti-tumor cytotoxic T cell function was enhanced in exercised mice, but these functional benefits were not observed when chronic stress was added. Notably, the decreased cytotoxicity results are correlated with increased PD-1 expression. Conclusions: Neither physical activity nor psychological stress reduced tumor growth once established; instead, they significantly increased tumor progression. Exercise did not appear to mitigate the impact of psychological stress on tumor growth or combat the negative impacts on anti-tumor immunity. However, our findings did suggest different stressors impact key anti-tumor immune cell numbers and functions that will need to be considered when developing treatment plans.

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“…Although our study focused primarily on periosteal cells, we also found that NE-Adrb2 signaling increased Vegfa expression in osteoblasts. Thus, it is likely that increased NE signaling induces the production of angiogenic factors not only in periosteal cells but also in other cell types during bone repair, as Adrb2 has been repeatedly shown to be a positive regulator of angiogenesis in many organ systems (52).…”

Section: Discussionmentioning

confidence: 99%

Increased beta2-adrenergic signaling is a targetable stimulus essential for bone healing by promoting callus neovascularization

Jahn,

Knapstein,

Otto

et al. 2023

Preprint

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Traumatic brain injury (TBI) is associated with a hyperadrenergic state and paradoxically causes systemic bone loss while accelerating fracture healing. Here, we identify the beta2-adrenergic receptor (Adrb2) as a central mediator of these skeletal manifestations. While the negative effects of TBI on the unfractured skeleton can be explained by the established impact of Adrb2 signaling on bone formation, Adrb2 promotes neovascularization of the fracture callus under conditions of high sympathetic tone, including TBI and advanced age. Mechanistically, norepinephrine stimulates the expression of Vegfa and Cgrp primarily in periosteal cells via Adrb2, both of which synergistically promote the formation of osteogenic type-H vessels in the fracture callus. Accordingly, the beneficial effect of TBI on bone repair is abolished in mice lacking Adrb2 or Cgrp, and aged Adrb2-deficient mice without TBI develop fracture nonunions despite high bone formation in uninjured bone. Pharmacologically, the Adrb2 antagonist propranolol impairs, and the agonist formoterol promotes fracture healing in aged mice by regulating callus neovascularization. Clinically, intravenous beta-adrenergic sympathomimetics are associated with improved callus formation in trauma patients with long bone fractures. Thus, Adrb2 is a novel target for promoting bone healing, and widely used beta-blockers may cause fracture nonunion under conditions of increased sympathetic tone.

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A Systematic Review on the Role of Adrenergic Receptors in Angiogenesis Regulation in Health and Disease

Cited by 7 publications

References 77 publications

Increased β ₂ -adrenergic signaling promotes fracture healing through callus neovascularization in mice

Increased β ₂ -adrenergic signaling promotes fracture healing through callus neovascularization in mice

Physical and Psychological Stressors Increase Breast Tumor Growth but Differentially Alter Tumor Immunity

Increased beta2-adrenergic signaling is a targetable stimulus essential for bone healing by promoting callus neovascularization

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A Systematic Review on the Role of Adrenergic Receptors in Angiogenesis Regulation in Health and Disease

Cited by 7 publications

References 77 publications

Increased β 2 -adrenergic signaling promotes fracture healing through callus neovascularization in mice

Increased β 2 -adrenergic signaling promotes fracture healing through callus neovascularization in mice

Physical and Psychological Stressors Increase Breast Tumor Growth but Differentially Alter Tumor Immunity

Increased beta2-adrenergic signaling is a targetable stimulus essential for bone healing by promoting callus neovascularization

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Increased β ₂ -adrenergic signaling promotes fracture healing through callus neovascularization in mice

Increased β ₂ -adrenergic signaling promotes fracture healing through callus neovascularization in mice