Chung Ho Yun, Lee Seok Jong, Lee Jong Min, Huh Seung, Kim Hyung Kee, Kwon O Hyun, Lim Hyun Ju, Oh Eun Jung, Kim Tae Jung, O Teresa M, Waner Milton
From the *Department of Plastic and Reconstructive Surgery, Kyungpook National University, School of Medicine, and †Vascular Anomalies Center, Kyungpook National University Hospital, Daegu, Korea; ‡Vascular Birthmark Institute of New York, Lenox Hill Hospitals, New York, NY; §Department of Dermatology, ∥Department of Radiology, and ¶Department of Vascular Surgery, Kyungpook National University, School of Medicine, Daegu, Korea; and #Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Winston-Salem, NC.
Ann Plast Surg. 2015 Sep;75(3):332-7. doi: 10.1097/SAP.0000000000000015.
The molecular pathophysiology of venous malformations (VMs), which are a type of vascular malformation, is poorly understood. Until now, it is known that VM lesions are related to the process of angiogenesis. Because angiogenesis is induced under hypoxic conditions, hypoxia is thought to be important in VM lesion formation. Therefore, we examined the implications of hypoxia on the biological behavior of VM vascular smooth muscle cells (VSMCs). In doing so, we investigated the expression patterns of hypoxia-inducible factor-1α (HIF-1α), which plays a key role in hypoxia-induced angiogenesis, to provide a further understanding of the molecular mechanisms involved in VM.
Vascular smooth muscle cells from 5 normal veins and 5 VM lesions were cultured under moderate hypoxic conditions (3% O2, 5% CO2). The effects of hypoxia on HIF-1α expression were measured by immunocytochemical staining, reverse transcription-polymerase chain reaction, and real-time reverse transcription-polymerase chain reaction.
Overall, the expression of HIF-1α in cells was high after exposure to hypoxia for 6 or 12 hours, but decreased after 24 hours of hypoxia. HIF-1α expression in VM VSMCs was 2 times higher than that in normal VSMCs. Immunocytochemically, HIF-1α was mainly located in the nucleus and the intensity in VM VSMCs was stronger after 6 and 12 hours of hypoxia when compared to the expression pattern of HIF-1α in VSMCs from normal tissue. This suggested that VM tissue is more susceptible to the effects of hypoxia than normal tissue.
These results indicate that the high expression of HIF-1α in VM VSMCs under hypoxic conditions could be an important factor for stimulating downstream angiogenesis in VM. Furthermore, the results of this investigation could provide the basis for future studies of VM pathophysiology, and ultimately lead to the development of new therapeutic approaches.
静脉畸形（VMs）作为一种血管畸形，其分子病理生理学仍知之甚少。到目前为止，已知VM病变与血管生成过程有关。由于血管生成在缺氧条件下被诱导，因此缺氧被认为在VM病变形成中起重要作用。因此，我们研究了缺氧对VM血管平滑肌细胞（VSMCs）生物学行为的影响。在此过程中，我们研究了缺氧诱导因子-1α（HIF-1α）的表达模式，HIF-1α在缺氧诱导的血管生成中起关键作用，以进一步了解VM中涉及的分子机制。
从5条正常静脉和5个VM病变中获取血管平滑肌细胞，在中度缺氧条件（3% O2，5% CO2）下培养。通过免疫细胞化学染色、逆转录-聚合酶链反应和实时逆转录-聚合酶链反应测量缺氧对HIF-1α表达的影响。
总体而言，细胞在缺氧6或12小时后HIF-1α表达较高，但在缺氧24小时后降低。VM VSMCs中HIF-1α的表达比正常VSMCs高2倍。免疫细胞化学显示，HIF-1α主要位于细胞核中，与正常组织VSMCs中HIF-1α的表达模式相比，缺氧6和12小时后VM VSMCs中的强度更强。这表明VM组织比正常组织对缺氧的影响更敏感。
这些结果表明，缺氧条件下VM VSMCs中HIF-1α的高表达可能是刺激VM下游血管生成的重要因素。此外，本研究结果可为未来VM病理生理学研究提供基础，并最终导致新治疗方法的开发。
