Do all types of hemangiomas, especially endothelial cells of those hemangiomas, express Beta 2 (beta-2) adrenergic receptors?

From the Guidelines

Not all types of hemangiomas express beta-2 adrenergic receptors in their endothelial cells, with infantile hemangiomas (IHs) being a specific type that expresses these receptors. The expression of beta-2 adrenergic receptors is significant in the context of treating infantile hemangiomas with propranolol, a non-selective beta-blocker, as it explains the drug's mechanism of action in these lesions 1. The presence of beta-2 adrenergic receptors on capillary endothelial cells in proliferating IHs suggests that propranolol works by vasoconstriction, inhibition of angiogenesis, and possibly induction of apoptosis through these receptors 1. Other vascular anomalies, such as congenital hemangiomas (including rapidly involuting congenital hemangioma [RICH] and non-involuting congenital hemangioma [NICH]), kaposiform hemangioendotheliomas, and venous malformations, have different molecular profiles and do not consistently express beta-2 receptors in the same manner as IHs 1. Key characteristics of these vascular anomalies include:

• Congenital hemangiomas are present and fully formed at birth and do not exhibit the postnatal proliferative phase characteristic of IHs 1.
• RICHs undergo a rapid involution phase beginning in the first year of life, while NICHs remain stable without growth or involution 1.
• Kaposiform hemangioendotheliomas and venous malformations have distinct clinical and molecular features that differentiate them from IHs 1. Understanding the differential expression of beta-2 adrenergic receptors across various vascular anomalies is crucial for explaining why beta-blockers are not equally effective for all types of hemangiomas or vascular malformations 1.

From the Research

Expression of Beta 2 Adrenergic Receptors in Hemangiomas

• The expression of beta 2 adrenergic receptors in hemangiomas, especially endothelial cells, has been studied in various research papers 2, 3, 4, 5.
• A study published in 2012 found that all phases of infantile hemangiomas had strong expression of beta 2 adrenergic receptors, with the exception of only weak expression of beta 2 adrenergic receptor phosphorylated form in the proliferative phase infantile hemangioma 2.
• Another study published in 2017 found that there was no difference in beta 2 adrenergic receptor expression among proliferative, involuted, and propranolol-responsive hemangioma groups 3.
• A study published in 2013 found that both beta 1 and beta 2 adrenergic receptors were co-localized in endothelial cells and pericytes of infantile hemangiomas, and that propranolol responsiveness was not determined by qualitative differences in adrenergic receptors 4.
• A study published in 2016 found that hemangioma stem cells express beta 1 and beta 2 adrenergic receptors, and that propranolol acts on these cells to suppress proliferation and promote apoptosis via beta 2 adrenergic receptor perturbation 5.
• A study published in 2019 found that propranolol exhibits activity against hemangiomas independent of beta blockade, and that the beta blockade inactive R-propranolol isomer can downregulate Angiopoietin-like 4 (ANGPTL4) in endothelial cells and inhibit the growth of hemangioma cells in vivo 6.

Endothelial Cell Expression

• Endothelial cells of hemangiomas have been found to express beta 2 adrenergic receptors in several studies 2, 4, 5.
• The expression of beta 2 adrenergic receptors in endothelial cells has been found to be strong in infantile hemangiomas, especially in the proliferative phase 2.
• The co-localization of beta 1 and beta 2 adrenergic receptors in endothelial cells and pericytes of infantile hemangiomas has been found to be a characteristic feature of these tumors 4.

Clinical Implications

• The expression of beta 2 adrenergic receptors in hemangiomas, especially endothelial cells, has clinical implications for the treatment of these tumors with propranolol 2, 3, 4, 5.
• The use of propranolol as a treatment for infantile hemangiomas has been found to be effective, and the expression of beta 2 adrenergic receptors in these tumors may play a role in this effectiveness 2, 3, 4, 5.
• Further research is needed to fully understand the role of beta 2 adrenergic receptors in hemangiomas and to develop more targeted therapies for these tumors 5, 6.