Clyman R I, Chan C Y, Mauray F, Chen Y Q, Cox W, Seidner S R, Lord E M, Weiss H, Waleh N, Evans S M, Koch C J
Cardiovascular Research Institute, Department of Pediatrics, University of California, San Francisco 94143-0544, USA.
Pediatr Res. 1999 Jan;45(1):19-29. doi: 10.1203/00006450-199901000-00005.
Permanent closure of the ductus arteriosus requires loss of cells from the muscle media and development of neointimal mounds, composed in part of proliferating endothelial cells. We hypothesized that postnatal ductus constriction produces hypoxia of the inner vessel wall; we also hypothesized that hypoxia might lead to cell death and the production of vascular endothelial cell growth factor (VEGF), a hypoxia-inducible growth factor that stimulates endothelial proliferation. We mapped the distribution of hypoxia in newborn baboons and correlated it with the appearance of cell death (TUNEL technique), VEGF expression, and endothelial proliferation (proliferating cell nuclear antigen expression). In the full-term baboon (n=10), the ductus was functionally closed on Doppler examination by 24 h after delivery. Regions of the ductus where the lumen was most constricted were associated with moderate/intense hypoxia; VEGF expression was increased in the hypoxic muscle media, and luminal endothelial cells, adjacent to the hypoxic media, were proliferating. Cells in the most hypoxic regions of the ductus wall were undergoing DNA fragmentation. In contrast, regions of the ductus with mild degrees of hypoxia had no evidence of cell death, VEGF expression, or endothelial proliferation. Cell death and endothelial proliferation seemed to be limited to regions of the full-term ductus experiencing moderate/intense hypoxia. In the premature baboon (67% gestation) (n=24), only 29% closed their ductus by Doppler examination before d 6. None of the premature baboons, including those with a closed ductus by Doppler, had evidence of moderate/intense hypoxia; also, there was no evidence of cell death, VEGF expression, endothelial proliferation, or neointima formation by d 6. Therefore, the premature ductus is resistant to developing hypoxia, even when its lumen is constricted; this may make it susceptible to later reopening.
动脉导管的永久性关闭需要中膜肌肉细胞的丢失以及新生内膜丘的形成，新生内膜丘部分由增殖的内皮细胞组成。我们推测出生后动脉导管的收缩会导致血管内壁缺氧；我们还推测缺氧可能导致细胞死亡并产生血管内皮生长因子（VEGF），VEGF是一种缺氧诱导生长因子，可刺激内皮细胞增殖。我们绘制了新生狒狒缺氧的分布情况，并将其与细胞死亡（TUNEL技术）、VEGF表达以及内皮细胞增殖（增殖细胞核抗原表达）的出现情况进行关联。在足月狒狒（n = 10）中，出生后24小时通过多普勒检查发现动脉导管功能关闭。动脉导管中管腔最狭窄的区域与中度/重度缺氧相关；缺氧的中膜肌肉层中VEGF表达增加，与缺氧中膜相邻的管腔内内皮细胞正在增殖。动脉导管壁缺氧最严重区域的细胞正在发生DNA片段化。相比之下，轻度缺氧的动脉导管区域没有细胞死亡、VEGF表达或内皮细胞增殖的迹象。细胞死亡和内皮细胞增殖似乎仅限于足月动脉导管中经历中度/重度缺氧的区域。在早产狒狒（妊娠67%）（n = 24）中，在第6天之前通过多普勒检查只有29%的动脉导管关闭。所有早产狒狒，包括那些通过多普勒检查显示动脉导管已关闭的，在第6天均没有中度/重度缺氧的迹象；同样，也没有细胞死亡、VEGF表达、内皮细胞增殖或新生内膜形成的迹象。因此，早产的动脉导管即使管腔收缩也不易发生缺氧；这可能使其日后易于重新开放。
