**4. Highlights on vascular development under hypoxia or normoxia in the chicken model**

Angiogenesis in the mature pulmonary circulation could be a structural adaptation that may have important beneficial consequences for gas exchange (Howell et al., 2003). In contrast, Yamamoto et al (2008) reported a chronic hypoxia-induced pulmonary blood vessels loss, an event sometimes called "rarefaction" or "pruning".

Although there is no definitive evidence of less vascularized areas in the avian lung, it is feasible that during hypoxia, vasculogenesis and angiogenesis occur to augment the gas exchange area. Hypoxia exposure for 3 to 4 weeks, does not affect pulmonary growth in current commercial chicken strains (Vásquez and Hernández, 2011; Areiza et al., 2011). These findings appear to be controversial, since alveolar and vascular neo-formation should both increase in the pulmonary response to hypoxia (reviewed by Bhattacharya, 2008). If this is not the case, less vascularized areas within the lung could gain new blood vessels, which might not significantly affect the whole organ´s weight. It should be noticed that arteriogenesis might also play a role in neo-vascularization (Deindi and Schaper, 2008)

The final goal of angiogenesis in the lung, should be to construct a complete functional arteriovenous tree. Therefore, vascular density would be represented by different types of blood vessels, such as arterioles or pre-capillaries. In this framework, using the chicken as a model, quantitative and molecular studies were undertaken to test the potentiality of hypobaric hypoxia to induce angiogenesis, to detect possible differences in vascular density in pulmonary hypertensive chickens and to correlate these findings with mRNA expression of some key genes for angiogenesis. Under hypobaric hypoxic conditions (altitude 2638 m above sea level, (oxygen tension: approximately 111 mmHg), both, healthy and pulmonary hypertensive birds, had more blood vessels with diameter ranges between >100-200, >200-300 and >300-500 µm, as compared to healthy chickens maintained under relative, normobaric, normoxic conditions (460 meters above sea level (oxygen tension: approximately 152 mmHg). However, the opposite was encountered when comparing values obtained for blood vessels within the ≥50-100 µm range. Coincident with this result, decreased expression of hepatocyte growth factor (HGF), HIF-2α, VEGF, Flk-1, and HGFR genes was encountered in the lung of chickens exposed to hypoxia. The same mRNA expression pattern did not show coincidence with observations for blood vessels within the range of 100-500 µm (Areiza et al., 2011, 2012).

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

Angiogenesis and Pulmonary Hypertension http://dx.doi.org/10.5772/56054 109

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

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

Facultad de Medicina Veterinaria y de Zootecnia, Universidad Nacional de Colombia, Bogotá,

[1] Abdollahi, A, Hahnfeldt, P, Maercker, C, et al. (2004). Endostatin`s Antiangiogenic

[2] Al-ruyabe, A. A. K, Kirshnamoorthy, S, Anthony, N. B, et al. (2010). Genetic Analysis Of Pulmonary Hypertension And Ascites In The Chicken. Plant & Animal Genomes

[3] Alvarez, D. F, Huang, L, King, J. A, et al. (2007). Lung microvascular endothelium is enriched with progenitor cells that exhibit vasculogenic capacity. American Journal

[4] Areiza, R. A, Rivas, P. C, & Hernández, A. (2011). A Quantitative Study of the Pul‐ monary Vascular Bed and Pulmonary Weight : Body Weight Ratio in Chickens Ex‐

of Physiology and Lung Cell and Molecular Physiology L, 419-430.

to depend on genetic differences and/or time of exposure to hypoxic conditions.

and Rafael A. Areiza

\*Address all correspondence to: ahernandezv@unal.edu.co

Signaling Network. Molecular Cell , 13, 649-663.

XVIII Conference. XVIII-W492.

concentrations within the lung, which change in the hypoxic lung.

(reviewed by Rey and Semenza, 2010).

**Author details**

Colombia

**References**

Aureliano Hernández\*

It is interesting that the mRNA expression of various genes compromised in both, angiogenesis and vascular remodeling, varies in pulmonary hypertensive (susceptible chickens) versus nonpulmonary hypertensive chickens, which indicates different degrees of resistance or suscept‐ ibility to hypobaric hypoxia (Gómez et al, 2007, 2008; Areiza et al., 2012). This coincidence reinforces the idea that among all the known compensatory mechanisms for low pO2 in the airways and hypoxemia, angiogenesis is one of them, but it might be a long term one.
