Lee D, Boscolo E, Durham J T, Mulliken J B, Herman I M, Bischoff J
Vascular Biology Program and Department of Surgery, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, U.S.A.
Br J Dermatol. 2014 Nov;171(5):1129-37. doi: 10.1111/bjd.13048. Epub 2014 Aug 28.
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.
To assess a possible role for haemangioma-derived pericytes (HemPericytes) isolated from proliferating and involuting phase tumours in apparent propranolol-induced vasoconstriction.
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.
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.
These findings suggest that the mechanism of propranolol's effect on proliferating IH involves increased pericytic contractility.
普萘洛尔是一种β-肾上腺素能受体（AR）拮抗剂，是治疗危及生命的婴儿血管瘤（IH）的有效药物。在开始普萘洛尔治疗后短时间内，常可见皮肤颜色显著变淡，数周至数月后可观察到IH血管加速消退。
评估从增殖期和消退期肿瘤中分离出的血管瘤源性周细胞（HemPericytes）在普萘洛尔诱导的明显血管收缩中可能发挥的作用。
在可变形的硅酮基质上检测HemPericytes的收缩性：普萘洛尔（10 μmol L⁻¹）可使因AR激动剂肾上腺素而松弛的HemPericytes恢复基础收缩水平。β2-AR的小干扰RNA敲低减弱了这种反应。将HemPericytes和血管瘤源性内皮细胞皮下共植入裸鼠体内以形成血管；注射后第7天，将小鼠随机分为溶剂对照组和普萘洛尔治疗组。
与阳性对照膀胱平滑肌细胞相比，HemPericytes表达高水平的β2-AR mRNA。此外，与β1-AR、β3-AR和α1b-AR相比，IH标本（n = 15）中的β2-AR mRNA水平相对较高。在此检测中，正常人视网膜和胎盘周细胞不受肾上腺素或普萘洛尔的影响。普萘洛尔（10 μmol L⁻¹）在体外抑制HemPericytes以及正常周细胞的增殖，表明在此检测中有非选择性作用。治疗7天后对植入物进行的对比增强微超声检查显示，普萘洛尔治疗的动物血管体积显著减小，而溶剂对照治疗的动物则无减小。
这些发现表明普萘洛尔对增殖期IH的作用机制涉及周细胞收缩性增加。
