IntroductionAngiogenesis, namely the formation of new vessels from preexisting ones, is essential for normal development, as well as for pathologic conditions, including tumor development, diabetic retinopathy, atherosclerosis, and rheumatoid arthritis. In recent years, endothelial apoptosis was shown to play an important role in remodeling the vascular network. Endothelial apoptosis is observed at the initiation of angiogenesis and at the branching and regression of neovessels. [1][2][3] Angiogenesis is controlled by the balance between proangiogenic factors and angiogenesis inhibitors, which also regulate apoptosis of endothelial cells (ECs). Indeed, the mechanism underlying many antiangiogenic therapies appears to be the induction of endothelial cell death. 4 Among the transcription factors involved in the regulation of angiogenesis and vascular development are members of the ETS family. This large family of transcription factors contains approximately 30 members that share a highly conserved DNA-binding domain (ETS domain) and are involved in regulating a wide variety of biologic processes. Many ETS proteins are expressed early in the developing vasculature in several organisms, and loss-of-function studies in mice and zebrafish have shown a critical role for ETS factors in vascular development. 5 In the adult, several endothelial ETS transcription factors were shown to regulate angiogenesis. 6 Among these, the ETS family member Erg is constitutively expressed in ECs, 7 and its expression is apparently restricted to ECs, megakaryocytes, 8 and chondrocytes. 9 Erg drives transcription of genes involved in endothelial homeostasis and angiogenesis, such as eNOS, 10,11 Data from animal models indicate that Erg is involved in endothelial differentiation and vascular development 12 ; for example, Erg overexpression in Xenopus embryos resulted in ectopic endothelial differentiation. 13 We have previously shown that Erg is required for angiogenesis in human ECs in vitro 14 ; however, no data are available on the role of Erg in angiogenesis in the adult in vivo.Endothelial junctions are crucial for the maintenance and regulation of vascular homeostasis and function and mediate a complex signaling network. 15 A major regulator of adherent junctions is vascular endothelial (VE)-cadherin, a Ca 2ϩ -dependent cell-surface adhesion molecule that forms homophilic interactions and is required for the integrity of the endothelial monolayer, endothelial permeability, and the control of cell growth. 16,17 VE-cadherin was clearly shown to regulate vascular development and angiogenesis: genetic inactivation of the VE-cadherin gene leads to early embryonic death because of vascular defects 18,19 and antibodies to VE-cadherin inhibit angiogenesis both in vitro and in vivo (reviewed in Dejana et al 20 ). VE-cadherin regulates a number of signaling events, by intracellular interaction with proteins of the armadillo family, including ␤-catenin and plakoglobin, as well as by clustering signaling molecules and growth factor receptors. 1...

Rationale: Senescence of pulmonary artery smooth muscle cells (PA-SMCs) caused by telomere shortening or oxidative stress may contribute to pulmonary hypertension associated with chronic lung diseases.Objective: To investigate whether cell senescence contributes to pulmonary vessel remodeling and pulmonary hypertension in chronic obstructive pulmonary disease (COPD). Methods and Results:In 124 patients with COPD investigated by right heart catheterization, we found a negative correlation between leukocyte telomere length and pulmonary hypertension severity. In-depth investigations of lung vessels and derived cultured PA-SMCs showed greater severity of remodeling and increases in senescent p16-positive and p21-positive PA-SMCs and proliferating Ki67-stained cells in 14 patients with COPD compared to 13 age-matched and sex-matched control subjects who smoke. Cultured PA-SMCs from COPD patients displayed accelerated senescence, with fewer cell population doublings, an increased percentage of ␤-galactosidase-positive cells, shorter telomeres, and higher p16 protein levels at an early cell passage compared to PA-SMCs from controls. Both in situ and in vitro PA-SMC senescence criteria correlated closely with the degree of pulmonary vessel wall hypertrophy. Because senescent PA-SMCs stained for p16 and p21 were virtually confined to the media near the Ki67-positive cells, which predominated in the neointima and hypertrophied media, we evaluated whether senescent cells affected normal PA-SMC functions. We found that senescent PA-SMCs stimulated the growth and migration of normal target PA-SMCs through the production and release of paracrine soluble and insoluble factors. Conclusion

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