Physiologic and molecular consequences of endothelial Bmpr2 mutation.
Physiologic and molecular consequences of endothelial Bmpr2 mutation.
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DOI：
10.1186/1465-9921-12-84
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发表时间：
2011-06-22
影响因子：
5.8
通讯作者：
West J
中科院分区：
文献类型：
--
作者：
Majka S;Hagen M;Blackwell T;Harral J;Johnson JA;Gendron R;Paradis H;Crona D;Loyd JE;Nozik-Grayck E;Stenmark KR;West J
肺动脉高压（PAH）被认为是由肺血管微内皮细胞（PMVEC）功能障碍驱动的。大多数遗传性多环芳烃与BMPR2突变有关。然而，BMPR2突变在PMVEC中表达的生理和分子后果尚不清楚。体内实验是在有条件的内皮特异性表达截断突变Bmpr2delx4+的成年小鼠身上进行的，并以年龄匹配的仅使用反激活剂的小鼠为对照。表型通过RVSP、肌肉化血管和增殖细胞计数、血栓、炎症细胞和凋亡细胞染色来评估。观察siRNA敲低PMVEC中BMPR2对细胞凋亡率的影响。采用Affymetrix表达阵列对从携带不朽小鼠基因、反激活因子和对照、Bmpr2delx4+或Bmpr2R899X突变的三重转基因小鼠分离和培养的PMVEC进行表达。转基因小鼠RVSP增加，小血管肌肉化，组织学改变包括血栓形成，炎症细胞增加，增殖细胞增加，凋亡细胞适度增加。表达阵列显示了与组织学变化一致的特定途径的改变。Bmpr2delx4+和Bmpr2R899X突变在增殖、凋亡、代谢和粘附方面导致非常相似的改变；Bmpr2delx4+细胞显示血小板粘附基因和细胞因子在Bmpr2R899X PMVEC中未见上调。与平滑肌细胞中的Bmpr2突变不同，PMVEC中的Bmpr2突变不会导致分化标记物的丢失。体内PMVEC中Bmpr2突变可能通过多种潜在独立的下游机制驱动PAH，包括增殖、凋亡、炎症和血栓形成。
Pulmonary arterial hypertension (PAH) is thought to be driven by dysfunction of pulmonary vascular microendothelial cells (PMVEC). Most hereditary PAH is associated with BMPR2 mutations. However, the physiologic and molecular consequences of expression of BMPR2 mutations in PMVEC are unknown. In vivo experiments were performed on adult mice with conditional endothelial-specific expression of the truncation mutation Bmpr2delx4+, with age-matched transactivator-only mice as controls. Phenotype was assessed by RVSP, counts of muscularized vessels and proliferating cells, and staining for thromboses, inflammatory cells, and apoptotic cells. The effects of BMPR2 knockdown in PMVEC by siRNA on rates of apoptosis were assessed. Affymetrix expression arrays were performed on PMVEC isolated and cultured from triple transgenic mice carrying the immortomouse gene, a transactivator, and either control, Bmpr2delx4+ or Bmpr2R899X mutation. Transgenic mice showed increased RVSP and corresponding muscularization of small vessels, with histologic alterations including thrombosis, increased inflammatory cells, increased proliferating cells, and a moderate increase in apoptotic cells. Expression arrays showed alterations in specific pathways consistent with the histologic changes. Bmpr2delx4+ and Bmpr2R899X mutations resulted in very similar alterations in proliferation, apoptosis, metabolism, and adhesion; Bmpr2delx4+ cells showed upregulation of platelet adhesion genes and cytokines not seen in Bmpr2R899X PMVEC. Bmpr2 mutation in PMVEC does not cause a loss of differentiation markers as was seen with Bmpr2 mutation in smooth muscle cells. Bmpr2 mutation in PMVEC in vivo may drive PAH through multiple, potentially independent, downstream mechanisms, including proliferation, apoptosis, inflammation, and thrombosis.
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影响因子：
37.8
作者：
Hong KH;Lee YJ;Lee E;Park SO;Han C;Beppu H;Li E;Raizada MK;Bloch KD;Oh SP
通讯作者：
Oh SP
DOI：
10.1073/pnas.88.12.5096
发表时间：
1991-06-01
影响因子：
11.1
作者：
JAT, PS;NOBLE, MD;KIOUSSIS, D
通讯作者：
KIOUSSIS, D
影响因子：
2.9
作者：
Bendall, AJ;Rincón-Limas, DE;Abate-Shen, C
通讯作者：
Abate-Shen, C
影响因子：
4
作者：
Paradis, Helene;Islam, Thasin;Gendron, Robert L.
通讯作者：
Gendron, Robert L.
DOI：
10.1152/ajpheart.00254.2009
发表时间：
2010-04-01
影响因子：
4.8
作者：
Rajkumar, Revathi;Konishi, Kazuhisa;Ahmad, Ferhaan
通讯作者：
Ahmad, Ferhaan