Propranolol targets the contractility of infantile haemangioma-derived pericytes.
BACKGROUND
Propranolol, a β-adrenergic receptor (AR) antagonist, is an effective treatment for endangering infantile haemangioma (IH). Dramatic fading of cutaneous colour is often seen a short time after initiating propranolol therapy, with accelerated regression of IH blood vessels discerned after weeks to months.


OBJECTIVE
To assess a possible role for haemangioma-derived pericytes (HemPericytes) isolated from proliferating and involuting phase tumours in apparent propranolol-induced vasoconstriction.


METHODS
HemPericytes were assayed for contractility on a deformable silicone substrate: propranolol (10 μmol L(-1)) restored basal contractile levels in HemPericytes that were relaxed with the AR agonist epinephrine. Small interfering RNA knockdown of β2-AR blunted this response. HemPericytes and haemangioma-derived endothelial cells were co-implanted subcutaneously in nude mice to form blood vessels; at day 7 after injection, mice were randomized into vehicle and propranolol-treated groups.


RESULTS
HemPericytes expressed high levels of β2-AR mRNA compared with positive control bladder smooth muscle cells. In addition, β2-AR mRNA levels were relatively high in IH specimens (n = 15) compared with β1-AR, β3-AR and α1b-AR. Normal human retinal and placental pericytes were not affected by epinephrine or propranolol in this assay. Propranolol (10 μmol L(-1)) inhibited the proliferation of HemPericytes in vitro, as well as normal pericytes, indicating a nonselective effect in this assay. Contrast-enhanced microultrasonography of the implants after 7 days of treatment showed significantly decreased vascular volume in propranolol-treated animals, but no reduction in vehicle-treated animals.


CONCLUSIONS
These findings suggest that the mechanism of propranolol's effect on proliferating IH involves increased pericytic contractility.
Vascular Biology Program and Department of Surgery, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, U.S.A.
D
D
Lee
E
E
Boscolo
J T
JT
Durham
J B
JB
Mulliken
I M
IM
Herman
J
J
Bischoff
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001810:Blood Volume; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D006391:Hemangioma / Q000098:blood supply / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D020286:Pericytes / Q000502:physiology*; D011433:Propranolol / Q000494:pharmacology*; D011897:Random Allocation; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D011433:Propranolol; D004837:Epinephrine