Biology Department, Utica University, Utica, New York, USA.
Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, New York, USA.
Animal Model Exp Med. 2023 Aug;6(4):362-368. doi: 10.1002/ame2.12343.
Genetic analysis in human patients has linked mutations in PIK3CA, the catalytic subunit of PI-3'Kinase, to sporadic incidences of vascular malformations.
We have developed a mouse model with inducible and endothelial-specific expression of PIK3CA , resulting in the development of vascular malformations. Systemic induction of this mutation in adult mice results in rapid lethality, limiting our ability to track and study these lesions; therefore, we developed a topical and local induction protocol using the active metabolite of tamoxifen, 4OH-T, on the ear skin of adults.
This approach allows us to successfully model the human disease in a mature and established vascular bed and track the development of vascular malformations. To validate the utility of this model, we applied a topical rapamycin ointment, as rapamycin is therapeutically beneficial to patients in clinical trials. We found that the induced ear lesions showed significant attenuation after treatment, which was easily quantified.
These data collectively provide evidence of a new model to study vascular malformations in adult tissues, which should be particularly useful in environments lacking specialized small-animal imaging facilities.
在人类患者中进行的遗传分析将 PIK3CA（PI-3'激酶的催化亚基）的突变与散发性血管畸形联系起来。
我们开发了一种具有可诱导和内皮特异性表达 PIK3CA 的小鼠模型，导致血管畸形的发展。在成年小鼠中全身性诱导这种突变会导致快速死亡，限制了我们追踪和研究这些病变的能力；因此，我们开发了一种使用他莫昔芬的活性代谢物 4OH-T 在成年耳朵皮肤进行局部诱导的方案。
这种方法使我们能够在成熟和已建立的血管床上成功模拟人类疾病，并追踪血管畸形的发展。为了验证该模型的实用性，我们应用了局部雷帕霉素软膏，因为雷帕霉素在临床试验中对患者具有治疗益处。我们发现，诱导的耳部病变在治疗后明显减轻，这很容易量化。
这些数据共同提供了一种在成年组织中研究血管畸形的新模型的证据，对于缺乏专门的小动物成像设施的环境尤其有用。
