The Maturation Phase of Angiogenesis Role of the Angiopoietin1Tie2 Pathway on Development of Pulmonary Hypertension

A critical aspect of vessel development is maturation, during which ECs no longer proliferate or migrate but instead promote vessel stabilization by recruiting peri-endothelial support cells, which differentiate into smooth muscle cells [14]. Because this maturation phase is partly under the control of angiopoietin-1 (Ang1), which acts selectively on ECs via the Tie2 receptor [8], one theory is that EC stimulation by Ang1 leads to the release of signaling molecules that act on smooth muscle cells [26,31]. In accordance with a role for such a mechanism in the pulmonary circulation, it was recently shown that ECs stimulated with Ang1 were capable of promoting PA-SMC growth [31]. In a more recent study, we obtained evidence that serum-free medium of quiescent human ECs elicited marked PA-SMC proliferation, although the ECs were not previously stimulated by Ang1 [12]. Interestingly, this effect was greater with ECs from patients with idiopathic PH than with ECs from controls, suggesting dysregulation of this mechanism in idiopathic PH. Thus, an intriguing hypothesis is that the angiopoietin/Tie2 pathway, which seems to play a role in normal vessel wall development, may be altered in idiopathic PH, thereby leading to excessive smooth muscle proliferation.

In recent studies we investigated the angiopoietin-1/Tie2 pathway in patients with idiopathic PH [9]. For this purpose, we sampled lung tissue from patients with idiopathic PH and controls and we investigated the expression of Ang1, Ang2, and Tie2 receptor in cultured PA-SMCs and in ECs, as well as in whole lung homogenates. Second, we investigated whether treatment of cultured ECs with Ang1 increased the growth-promoting activity of culture medium from ECs of patients and controls.

We found that the angiopoietin/Tie2 pathway effectively contributed to PA-SMC proliferation by stimulating the release of growth factors by ECs. The stimulating effect of EC media on PA-SMC growth was greater with ECs from patients with iPAH than from controls and treatment with Ang1 in both cases stimulated the PA-SMC growth-promoting activity of EC media. We found that Ang1 expression in PA-SMCs did not differ between patients with iPAH and controls, whereas the Ang1 receptor Tie2 was overexpressed in ECs from patients with idiopathic PH. Consequently, stimulation by

Ang1 of ECs from patients with iPAH increased the release of the signaling molecules such as serotonin and ET-1, which was less marked in ECs from controls. Taken together, these results suggest that the Ang1/Tie2 pathway is abnormal in idiopathic PH and contributes to PA-SMC hyperplasia.

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