**5. Final remarks**

Promoting angiogenesis, vasculogenesis, or arteriogenesis could represent a possible palliative treatment in individuals chronically exposed to hypobaric hypoxia. It is clear that it would be useful to establish some characteristics of vascular development in the lung of susceptible individuals subjected to chronic hypoxia, in order to design long term treatments, such as vascular neo-formation enhancement. In this context, it is desirable to further investigate the chronology of angiogenesis in the hypoxic lung.

Again, mesodermal derivatives particularly bone marrow cells, the endothelium, and fibro‐ blasts, act in two different but possibly complementary ways, as a response to hypoxia: the remodeling process and pulmonary vascular neo-formation. However, as has been presently highlighted, some results are controversial, which could not be currently explained, since there is not enough information on the vascular development in the lung, as a result of hypoxic exposure of susceptible and non-susceptible individuals, which would allow for the under‐ standing of the molecular framework of angiogenesis at different stages of development and possibly, the correspondent genes involved.

Angiogenesis is a distinct mechanism to compensate for the hypoxic conditions within the alveoli (or respiratory capillaries in birds). However, addition of new blood vessels to the lung as a compensatory mechanism, might be a time-dependent process, as it occurs in the placenta, where distinct factors intervene at different times during gestation (Hamilton et al., 1995; Athanassiades and Lala, 1998; Matsumoto et al., 2002; Wulff et al., 2002), and further studies are needed in this matter. Evidence in this direction was given by Sands et al (2011), as related to the adapting process to hypoxia. They found that the *in vivo* actions of VEGFB and PGF can either inhibit or potentiate the actions of VEGFA. Those effects depend on their relative concentrations within the lung, which change in the hypoxic lung.

At this point, it is noted that ET-1, one the most studied molecules, has been chosen as a target molecule, in works aimed to design PH alleviation, by blocking its A receptor with bosentan (Weber et al., 1996; Lim et al., 2009). Also, vasoactive intestinal peptide was found to be a more potent ET-1 A receptor blocking agent than bosentan (Hamidi et al., 2011). Stromal derived factor 1 (SDF1), angiopoietin 2 (ANGPT2), placental growth factor (PGF), platelet-derived growth factor B (PDGFB), and stem cell factor (SCF) are also included as target molecules (reviewed by Rey and Semenza, 2010).

It is clear that both, angiogenesis and vascular remodeling as seen in PH, share common biological pathways and the endothelium appears to be the main participating structure in this regard. This coincidence might be an advantage in the design of therapeutic measures.

Some apparent differences in quantitative findings related to vascular neo-formation appear to depend on genetic differences and/or time of exposure to hypoxic conditions.
