Mechanisms of vascular growth control in infantile hemangioma

• Applicant: Dr. Annegret Holm
• Subject Area: Pediatric and Adolescent Medicine ; General Genetics and Functional Genome Biology ; Dermatology ; Cell Biology
• Term: from 2021 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458322953

Vascular anomalies comprise a wide spectrum of innate and rare disorders that are attributed to focal disruption in vascular development processes. Two distinct entities are differentiated: vascular tumors and vascular malformations. Benign vascular tumors exhibit a high postnatal proliferative potential with spontaneous regression, while vascular are structural vascular anomalies grow proportionally with the individual. The understanding of the genetic background of vascular malformations has recently been advanced, whereas evidence for genetic origins in vascular tumors is still lacking.The most prominent example of benign vascular tumors are infantile hemangiomas (IH). Its unique life cycle provides a fascinating paradigm to unravel mechanisms of vascular growth control. Most IH can be left untreated, while those with high growth potential in critical locations are to be treated to avoid long-term consequences or even acute life-threatening conditions. Propranolol, a non-selective beta blocker, is the current treatment of choice. However, not all patients respond to propranolol and serious side effects are hypoglycemia, hypotension and bradycardia. Notably, the mechanism by which propranolol reduces vascular growth in IH is still unclear and warrants further investigation. Prof. Bischoff’s Lab has developed a hemangioma stem cell line (HemSC) which form IH when subcutaneously injected into nude mice. Furthermore, the Bischoff Lab published work that provides evidence that propranolol impacts the transcription factor SOX18 dependent differentiation of HemSC into hemangioma endothelial cells (HemEC) and hemangioma pericytes (HemPC). To this end, I plan to use a well-established model wherein nude mice with a dominant negative SOX18 mutation (SOX18 Ragged Opossum) are subcutaneously injected with human hemangioma-derived cells. Based on the novel discovery that SOX18 transcription factor drives a transcriptional program that causes vascular overgrowth in IH and that propranolol disrupts abnormal SOX18 activity to restore normal vascular function, the proposal is anticipated to have the following significant impacts: it will i.) dissect the function of SOX18 in IH vessel formation, ii.) identify SOX18 dimerization partners and downstream targets that drive vascular overgrowth in IH and iii.) determine if novel genetic mechanisms underlie IH by identifying gene fusions and small copy number variants (CNVs) upstream of SOX18 signaling.Taken together, the proposal will reveal novel molecular insights into how postnatal vascular overgrowth in IH occurs and how drugs involved in the disruption of SOX18 protein-protein-interaction restore vascular quiescence and may provide fundamental insights into the genetic background of IH.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Joyce E. Bischoff, Ph.D.