Open access

Angiogenesis and Pulmonary Hypertension

Written By

Aureliano Hernández and Rafael A. Areiza

Submitted: April 26th, 2012 Published: July 17th, 2013

DOI: 10.5772/56054

From the Edited Volume

Pulmonary Hypertension

Edited by Jean M. Elwing and Ralph J. Panos

Chapter metrics overview

2,020 Chapter Downloads

View Full Metrics

1. Introduction

The aim of this chapter is to present an overview of salient findings in human beings and animal models (particularly in the chicken), as related to known participating molecules in angiogenesis within the lung as a response to induced and natural environmental hypoxia, in the framework of the pathobiology of pulmonary hypertension (PH).

Hypoxic PH is now recognized as an important disease within the PH types. More than 140 million human beings are settled in geographical zones located 2500 m above sea level (Peñaloza and Arias, 2007). Animals which provide proteins for human consumption, have different degrees of susceptibility to develop PH, especially the commercial chicken, which is particularly prone to develop PH, either from hypoxia (Gómez et al., 2007, 2008; Vásquez and Hernández, 2011; Areiza et al, 2011 and others) or low temperatures (Pakdel et al., 2005; Pan et al., 2005). The chicken has been proposed as a model to study PH in humans (Al-Ruyabe et al., 2010; Wideman and Hamal, 2011).

Exposure to hypoxia has been reported to cause different effects on the pulmonary vasculature. These include increasing the extent of pulmonary vascular network, increased vascular tone, vascular remodeling and in some cases quantitative reduction of microvessels. Neo-formation of blood vessels in the lung, takes place through a mechanism not fully understood and often controversial. Remodeling of pulmonary arterioles has been thoroughly studied. It includes thickening of the medial muscle and adventitia layers. Many tasks have been directed to discover the role of the endothelium in maintaining pulmonary vascular tone and in the PH remodeling process. Endothelial dysfunction leads to chronically impaired production of vasodilators such as nitric oxide (NO) and prostacyclin along with prolonged over expression of vasoconstrictors such as endothelin-1 (ET-1). These changes affect vascular tone and promote vascular remodeling. Given that most of these mediators affect the growth of smooth muscle cells, an alteration in their production may facilitate the development of pulmonary vascular hypertrophy and structural remodeling, which are characteristic of PH (Budhiraja et al., 2004; Humbert et al., 2004; reviewed by Hernández and Sandino de, 2011).

Both processes, angiogenesis and remodeling of pulmonary arterioles, appear to share the participation of similar molecules. In fact, some of them, known to increase pulmonary blood vessels tone during hypoxic exposure, are also involved in generating pulmonary blood vessels. In this framework, three main research cellular targets can be identified: the endothelium, the smooth muscle cells of the wall of pulmonary arterioles and, adventitial connective tissue cells.

PH has been related with malfunction of potassium channels and over-regulation of calcium channels on the cell membrane of vascular muscle cells as well as endothelial dysfunction. The latter, as it pertains with decreasing NO and prostacyclin (vasodilators) delivering and increment of vasocontrictors, such as endothelin-1 (ET-1) Inagami et al., 1995; Voelkel and Tuder, 2000)

In adult subjects, angiogenesis could be taken as a compensatory process during hypoxic exposure. This process would be in addition to the well-known mechanisms of augmenting blood perfusion in less vascularized areas in the lung, hyperventilation and erythropoiesis. Those areas might be a potentially available area for de novo vascular formation. Human beings living in highlands, have developed a greater lung capacity through evolution, as an adaptive mechanism to hypobaric hypoxia (Frisancho, 1970). Also, high landers show increased lung capillary density than lowlanders, which was interpreted as an effect of hypoxia on angiogenesis (Bisschop et al, 2010).

Ooi et al (2000) and Howell et al (2002, 2003) determined that hypoxic hypoxia (10% oxygen) provoked augmentation in volume and total length in pulmonary blood vessels in rats, together with an increment in endothelial superficial area and cells numbers. In another work, chronically hypoxic rats, which exhibited a greater degree of vascular development through angiogenesis, had higher cardiac mass index values than the correspondent ones in animals subjected to hypoxia and hypercapnia or normoxia (Howell et al., 2004). In mice subjected to hypoxia, Pascaud et al (2003) gave evidence that inhibition of hypoxia-induced angiogenesis, enhanced the degree of PH.

Angiogenesis is regulated by angiogenic and anti-angiogenic molecules (Pascaud et al., 2003; Maharaj and D`Amore, 2007). Genetic and epigenetic factors permit blood vessels formation (Pauling and Vu, 2004). Taraseviciene-stewart et al (2001) found that plexiform lesions in idiopathic pulmonary hypertension (iPAH) were associated with disordered angiogenesis due to exaggerated mitosis of endothelial cells. Tuder and Voelkel (2002) reported endothelial cell proliferation in cases of primary PH, and, since these cells exhibited markers of angiogenesis, the authors named this process a "disordered or misguided angiogenesis”. In this context, endothelium progenitor cells are now claimed to be therapeutic targets in PH due to their possible involvement in PH pathobiology. Nitric oxide synthases (eNOs), vascular endothelial growth factor (VEGF), angiopoietins and their receptor tie-2, which are associated with vascular remodeling, were all expressed in a monocrotaline induced model of PH (Cho et al., 2009). Furthermore, induced ischemia results in pronounced cell proliferation and consequent lung vascularization in mice, within a period of 20 days (Wagner et al, 2006).

If vascular growth in the lung is an adapting mechanism to hypoxia, genetically predisposed individuals will develop hypoxic PH, and have a diminished pulmonary vascular growth capacity. Hence, angiogenesis might be the expression of genetic adaptation or predisposition to PH inducers.


2. Angiogenic promoting factors

The hypoxia inducible factor (HIF) system is oxygen sensitive. It includes HIF-1 and HIF-2. They bind and activate many of the same genes, but differ in their participation during hypobaric hypoxia. For instance, HIF-2 alone is responsible for the liberation of erythropoietin through stimulation of connective tissue cells in the kidney (Paliege et al., 2010) and other hematological reactions to hypoxia (reviewed by Tissot van Patot and Gassmann, 2011). HIF-1 is a key molecule in regulating the expression of several angiogenic molecules. Among the hypoxia-inducible genes which have important HIF-1 binding sites and are believed to participate in the pathogenesis of PH and angiogenesis as well, are those encoding VEGF (Liu et al., 1995), the VEGF receptor 1 (Gerber et al, 1997), and ET-1 (Hu et al., 1998). Expression of VEGF and its receptor Fetal Liver Kinase 1 receptor (FLK-1) was enhanced in hypoxic pulmonary hypertensive rats (Christou et al., 1998). Rats maintained under hypoxic hypoxia (exposure to 10% oxygen) showed augmented volume and total length of pulmonary blood vessels (Howell et al. 2002, 2003; Ooi et al., 2000). In another study, rats exposed to hypobaric hypoxia, exhibited reduced Angiopoietin-1/Tie2 and VEGF expression, together with a diminished number of arterial blood vessels in the lung (Yamamoto et al., 2008).

Sands et al (2012) gave insight on the interaction of members of the VEGF family in hypoxic PH. They found that VEGFB and the placental growth factor (PGF) inhibit or potentiate the actions of VEGFA, according to their relative concentrations, which change in the lungs of rats subjected to hypoxic hypoxia. The same authors stated that the abovementioned effects in vivo depend on specific concentrations of VEGF and PGF within the alveolar wall during adaptation to hypoxia. In this context, human subjects developing acute mountain sickness had higher levels of plasma VEGF on ascend to altitude as compared to their own values obtained under normoxic conditions. This variation did not occur in healthy subjects (Tissot van Patot et al., 2005).

VEGF exerts its angiogenic effect through four different pathways, which include NO participation (proposed by Gramatikoff, 1999). In a previous study, adrenomedullin mRNA expression was greater in the lungs of chickens with pulmonary hypertension compared with those without pulmonary hypertension (Gómez et al., 2008) and Vadivel et al (2010) demonstrated that adrenomedullin promotes angiogenesis in the lung. Hence, two vasodilators of pulmonary blood vessels, NO and adrenomedullin, may also have angiogenic properties.

Fahra et al (2011) found that CD34(+) and CD133(+) progenitor cell numbers are higher in the bone marrow, blood, and pulmonary arteries of pulmonary hypertensive subjects as compared to healthy controls. The blood levels of (hypoxia inducible myeloid-activating factors such as erythropoietin, the stem cell factor (SCF), and hepatocyte growth factor (HGF) were higher than normal levels in diseased individuals, and related to PH severity. Similarly, Davie et al (2004) found that progenitor cells from bone marrow origin contribute to neo-vascularization in pulmonary arteries of hypoxic calves, based on quantitative morphometric analyses of lung tissue from normoxic and hypoxic individuals. Their results showed adventitial growth in vasa vasorum of pulmonary arteries. This change was attributed to the transformation of cells from the bone marrow, which would be mobilized into the circulation, and differentiate into endothelial and smooth muscle cells. This model was supposed to entail an increase in the expression of c-kit(+), VEGF, fibronectin, and thrombin, as responses to hypoxia.

PH is linked to myeloid abnormalities, some of which may be related to increased production of HIF-inducible factors by a diseased pulmonary vasculature, but findings in non-affected subjects, suggest that myeloid abnormalities may be intrinsic to the disease process. Pro-angiogenic cell progenitors, and endothelial cells that have pathologic expression of hypoxia-inducible factor 1 alpha (HIF-1 alpha), were shown to be quantitatively higher in PH bone marrow, blood, and pulmonary arteries than in healthy controls. Also, the HIF-inducible myeloid-activating factors erythropoietin, stem cell factor (SCF), and hepatocyte growth factor (HGF) showed higher than normal levels in blood of pulmonary hypertensive subjects, and related to disease severity (Samar et al., 2011). In addition, endothelial progenitor cells with angiogenic capacity were found in the pulmonary circulation (Yoder, 2011). Epidermal growth factor promotes both angiogenesis and vascular remodeling (Janakidevi et al., 1995; Toby et al., 2010).

Bone morphogenetic protein (BMP) is compromised in endothelial repair within the pulmonary microvessels, and its expression is reduced in hypoxic PH, due to an increment in endothelial cell-derived Gremlin 1 and Gremlin 2, which antagonize BMP 2 type receptor expression (Cahill et al., 2012).


3. Inhibitors of angiogenesis

Angiogenesis is inhibited by thrombospondin-1 (TSP-1), a molecule produced by endothelial cells. Its secretion is induced by hypoxia and, experimentally, by NO inhibitors. In mesangial and smooth muscle cells, the cyclic guanosine monophosphate (GMPc) and kinase GMPc dependent protein, negatively regulate TSP-1 expression. CD36, a TSP-1 receptor, inhibits endothelial cell quimiotaxis (Isenberg el al., 2005). Low doses of NO stimulate endothelial cell proliferation, their motility and adhesion to collagen I matrixes, but the opposite is true for correspondent high doses. Exogenous TSP-1 treatment inhibits endothelial cell motility (Isenberg et al., 2005) and suppresses the angiogenic response provoked by low dose NO treatment (Ridnour et al., 2005).

Endogenous endostatin inhibits angiogenesis (Wickstrom et al., 2002; Paddenberg et al., 2006); it blocks the G1 phase of the cell cycle in endothelial cells, the attachment of VEGF165 and VEGF121 to the receptor VEGFR2 (Ribatti, 2009), and triggers endothelial cell apoptosis (Dhanabal et al., 1999). Endostatin interferes with the assembly of the actin cytoskeleton of endothelial cells and inhibits their proliferation and participation in angiogenesis (Abdollahi et al., 2004; Skovseth et al., 2005). Endostatin expression on the surface of the smooth muscle cells of pulmonary arterioles in the mouse, is provoked by hypoxic exposure (Paddenberg et al., 2006). NO, in culture, induces endostatin production. Hence, endothelial apoptosis is also induced (Deininger et al., 2003). In human endothelial cell cultures, addition of endostatin reduces angiogenic activity by reducing HIF-1α, VEGF, VEGFR2, HGH and EGFR gene expression. Furthermore, expression of some anti-angiogenic genes, such HIF1An (a HIF antagonist), Kininogen, TSP-1 and a Vasostatin precursor is increased (Abdollahi et al., 2004). However, it appears that the mode of action of endostatin, in this context, needs to be fully elucidated (Deininger et al., 2003; Skovseth et al., 2005).

Adiponectin (ADPN) reinforces the vasodilatory action of NO in pulmonary blood vessels (Summer et al, 2009), and as stated, if NO contributes to the control of angiogenesis, ADPN will be a potential inhibitor of vascularization. Also, Le Cras et al (2003) found that alpha transforming growth factor (TGF-α) overexpression induced a diminution in pulmonary vascular development, which was accompanied by severe PH and vascular remodeling.

Oxidative stress is higher in the lungs of pulmonary hypertensive chickens (Iqbal y col., 2001a, b), which has been associated, in another species, with decreasing numbers of blood vessels (Murfee and Schmid-Schonbein, 2008). Oxidative stress, occurring in chronically hypoxic mice, can enhance endostatin production (Deininger et al., 2003) (Paddenberg et al., 2006).


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 arterio-venous 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).

It is interesting that the mRNA expression of various genes compromised in both, angiogenesis and vascular remodeling, varies in pulmonary hypertensive (susceptible chickens) versus non-pulmonary hypertensive chickens, which indicates different degrees of resistance or susceptibility 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.


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 fibroblasts, 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 understanding 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.


  1. 1. AbdollahiAHahnfeldtPMaerckerCet al2004Endostatin`s Antiangiogenic Signaling Network. Molecular Cell 13649663
  2. 2. Al-ruyabeA. A. KKirshnamoorthySAnthonyN. Bet al2010Genetic Analysis Of Pulmonary Hypertension And Ascites In The Chicken. Plant & Animal Genomes XVIII Conference. XVIII-W492.
  3. 3. AlvarezD. FHuangLKingJ. Aet al2007Lung microvascular endothelium is enriched with progenitor cells that exhibit vasculogenic capacity. American Journal of Physiology and Lung Cell and Molecular Physiology L419430
  4. 4. AreizaR. ARivasP. CHernándezA2011A Quantitative Study of the Pulmonary Vascular Bed and Pulmonary Weight : Body Weight Ratio in Chickens Exposed to Relative Normoxia and Chronic Hypobaric Hypoxia. The journal of poultry science 484267274
  5. 5. AreizaRCaminosJ. EHernándezA2012Diminished pulmonary expression of hypoxia-inducible factor 2-alpha, vascular endothelial growth factor and hepatocyte growth factor in chickens exposed to chronic hypobaric hypoxia. The journal of poultry science. 49205211
  6. 6. AthanassiadesALalaP1998Role of placenta growth factor (PlGF) in human extravillous trophoblast proliferation, migration and invasiveness. Placenta 17545555
  7. 7. BhattacharyaJ2008Lung neovascularization: a tale of two circulations Am J Physiol Lung Cell Mol Physiol March 2008 294:L417L418
  8. 8. BisschopD. E. CKigerLMardenM. C2010Pulmonary capillary blood volume and membrane conductance in Andeans and lowlanders at high altitude: A cross-sectional study. Nitric Oxide 23187193
  9. 9. BudhirajaRTuderR. MHassounP. M2004Endothelial dysfunction in pulmonary hypertension. Circulation, 109159165
  10. 10. CahillECostelloC. MRowanS. Cet al2012Gremlin Plays a Key Role in the Pathogenesis of Pulmonary Hypertension. Circulation: 1257920U241.
  11. 11. ChoY. JHanJ. YLeeS. Jet al2009Temporal changes in angiopoietins and tie expression in rat lungs after monocrotaline-induced pulmonary hypertension. Comparative medicine. 59350356
  12. 12. ChristouHYoshidaAArthurVMoritaTand KourembanasS1998Increased vascular endothelial growth factor production in the lungs of rats with hypoxia-induced pulmonary hypertension. American Journal of Respiratory and Cell Molecular Biology 18768776
  13. 13. DhanabalMRamchandranRM. JWatermanM.J., et al1999Endostatin induces endothelial cell apoptosis. Journal of Biological Chemistry 2741172111726
  14. 14. DavieN. JCrossnoJ. TFridM. Get al2004Hypoxia-induced pulmonary artery adventitial remodeling and neovascularization: contribution of progenitor cells. American Journal of Physiology-Lung Cellular and Molecular Physiology 286: L668678
  15. 15. DeiningerM. HWybranietzW. AGraeplerF. T. Cet al2003Endothelial endostatin release is induced by nitric oxide/cGMP pathway. The FASEB Journal, 1712671276l
  16. 16. DeindiESchaperW2005The art of arteriogenesis. Cell biochemistry and biophysics 43115
  17. 17. FarhaSAsosinghKX. U, W. L2011Hypoxia-induciblefactors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalities. Blood 11734853493
  18. 18. FrisanchoA. R1970Developmental responses to high altitude hypoxia. American Journal of Physical Anthropology 32.401407
  19. 19. GerberHPCondorelliFParkJFerraraN. 1997Differential transcriptional regulation of the two vascular endothelial growth Factor receptor genes: Flt-1, but not Flk-1, is upregulated by hypoxia. Journal of Biological Chemistry 2722365923667
  20. 20. GómezA. PMorenoM. JIglesiasAet al2007Endothelin 1, its endothelin type a receptor, connective tissue growth factor, platelet-derived growth factor, and adrenomedullin expression in lungs of pulmonary hypertensive and nonhypertensive chickens. Poultry Science 86909916
  21. 21. GómezA. PMorenoM. JBaldrichR. MHernándezA2008Endothelin-1 Molecular Ribonucleic Acid Expression in Pulmonary Hypertensive and non-hypertensive Chickens. Poultry Science 8713951401
  22. 22. HamidiS. ALinR. Zet al2011VIP and endothelin receptor antagonist: An effective combination against experimental pulmonary arterial hypertension. Respiratory Research 12141147
  23. 23. HamiltonGLysiakJWatsonALalaP1995Autocrine growth stimulatory role of CSF-1 for the first trimester human trophoblast. American Journal of Reproductive Immunology 33316322
  24. 24. HernándezASandino de M., 2011Hypoxic pulmonary hypertension in the chicken model. In: Pulmonary hypertension. From bench research to clinical challenges. Edited by: Sulica, R., Preston, I. IntechRijeka, Croatia, 111150
  25. 25. HowellKHopkinsNMcloughlinP2002Combined Confocal Microscopy and Stereology: a Highly Efficient and Unbiased Approach to Quantitative Structural Measurement in Tissues. Exp Physiol. 876747756
  26. 26. HowellKPrestonR. JMcloughlinP2003Chronic hypoxia causes angiogenesis in addition to remodelling in the adult rat pulmonary circulation. Jornal of Physiology (Lond). 547133145
  27. 27. HuJDischerD. JBishopricN. HWebsterK. A1998Hypoxia regulates expression of endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand. Biochemical and biophysical research communications 245894899
  28. 28. HumbertMSilbonOSimonneauG2004Treatment of pulmonary arterial hypertension. New England Journal of Medicine 35114251436
  29. 29. InagamiTMitsuhideNHooverR1995Endothelium as an endocrine organ. Annual Reviews of Physiology 57171189
  30. 30. IqbalMCawthonDWidemanR. F J. RBottjeW. G2001aLung mitochondrial dysfunction in pulmonary hypertension syndrome. I. Site-specific defects in the electron transport chain. Poultry Science 80485495
  31. 31. IqbalMCawthonDWidemanR. F J. RBottjeW. G2001bLung mitochondrial dysfunction in pulmonary hypertension syndrome. II. Oxidative stress and inability to improve function with repeated additions of adenosine diphosphate. Poultry Science, 80656665
  32. 32. InagamiTMitsuhideNHooverR1995Endothelium as an endocrine organ. Annual Reviews of Physiology 57171189
  33. 33. IsenbergJ. SRidnourL. APerruccioE. Met al2005Thrombospondin-1 Inhibits Endothelial Cell Responses to Nitric Oxide in cGMP-Dependent Manner. Proceedings of the Natural Academy of Science. USA.1021314113146
  34. 34. JanakideviKTiruppathiCdel Vecchio, P.J., et al. 1995Growth characteristics of pulmonary artery smooth muscle cells from fawn-hooded rats Am J Physiol Lung Cell Mol Physiol March 1, 1995 268:L465L470
  35. 35. Le crasT. D., hardie, W. D., fagan, K., et al. 2003Disrupted Pulmonary Vascular Development and Pulmonary Hypertension in Transgenic Mice Overespressing Transforming Growth Factor-α. American Journal of Physiology Lung and Cellular Molecular Physiology 285: l1046l1054.
  36. 36. Le CrasT. D., Hardie, W. D., Fagan, K., et aL. 2003Disrupted Pulmonary Vascular Development and Pulmonary Hypertension in Transgenic Mice Overespressing Transforming Growth Factor-α. American Journal of Physiology Lung and Cellular Molecular Physiology 2851046l1054.
  37. 37. LimK. AShimJ. YChoS. HKimKCh., Han, J.J., Hong, Y.M. 2009Effect of endothelin receptor blockade on monocrotaline-induced pulmonary hypertension in rats. Korean J Pediatr. 52689695
  38. 38. LiuYCoxS. RMoritaTKourembanasS1995Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Circulation Research 77638643
  39. 39. MaharajA. S. RDAmoreP.A. 2007Roles for VEGF in the Adult. Microvascular Research 74100113
  40. 40. MatsumotoHM. A, WDaikokuT, et al. 2002Cyclooxygenase-2 differentially directs uterine angiogenesis during implantation in mice. Journal of Biological Chemistry 2772926029267
  41. 41. MelilloGMussoTSicaAet al1995A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. Journal of Experimental Medicine 18216831693
  42. 42. MurfeeW. LSchmid-schonbeinG. W2008Structure of microvascular networks in genetic hypertension. Methods in Enzymology, 444271284
  43. 43. OoiHCadoganESweeneyMet al2000Chronic hypercapnia inhibits hypoxic pulmonary vascular remodeling. Am. J. Physiol. Heart Circ. Physiol. 278: H331H338.
  44. 44. PaddenbergRFaulhammerPGoldenbergAKummerW2006Hypoxia-induced increase of endostatin in murine aorta and lung. Histochemistry and Cell Biology, 125497508
  45. 45. PakdelAVan ArendonkJ. AVereijkenA. LBovenhuisH2005Genetic parameters of ascites-related traits in broilers: effect of cold and normal temperature conditions. British Poultry Science 4613542
  46. 46. PaliegeARosenbergerCBondkeAet al2010Hypoxia-inducible factor-2alpha-expressing interstitial fibroblasts are the only renal cells that express erythropoietin under hypoxia-inducible factor stabilization. Kidney International 774312318
  47. 47. PanJ. QTanXLI J.C., et al2005Effects of early feed restriction and cold temperature on lipid peroxidation, pulmonary vascular remodelling and ascites morbidity in broilers under normal and cold temperature. British Poultry Science 463374381
  48. 48. PascaudM. AGriscelliFRaoulWet al2003Lung Overexpression of Angiostatin Aggravates Pulmonary Hypertension in Chronically Hypoxic Mice. American Journal of Respiratory and Cell Molecular Biology 29449457
  49. 49. PaulingMVuT. H2004Mechanisms and Regulation of Lung Vascular Development. Current Topics in Developmental Biology 647399
  50. 50. PeñalozaDAriasS. J2007The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness. Circulation 1159113246
  51. 51. ReySSemenzaG. L2010Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovascular research 86236242
  52. 52. RidnourL. AIsenbergJ. SEspeyM. Get al2005Nitric Oxide Regulates Angiogenesis Through a Functional Switch Involving Thrombospondin-1. Proceedings of the Natural Academy of Science. USA. 1021314713152
  53. 53. SamarFKewallAWeilingXet al2011Hypoxia-inducible factors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalities. Blood 11734853493
  54. 54. SandsMHowellKCostelloC. MMcloughlinP2011Placental growth factor and vascular endothelial growth factor B expression in the hypoxic lung. Respiratory Research 121729
  55. 55. SkovsethD. KVeugerM. J. TSorensenD. Ret al2005Endostatin Dramatically Inhibits Endothelial Cell Migration, Vascular Morphogenesis, and Perivascular Cell Recruitment in vivo. Blood. 10510441051
  56. 56. SummerRFiackC. AIkedaYet al2009Adiponectin deficiency: a model of pulmonary hypertension associated with pulmonary vascular disease. American Journal of Physiology and Lung Cell Molecular Physiology 297:L432438
  57. 57. Taraseviciene-stewartLKasaharaYAlgerLet al2001Inhibition of the vegf receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB Journal15427438
  58. 58. Tissot van Patot MC., Leadbetter G., Keyes, L.E., et al. 2005Greater free plasma VEGF and lower VEGF receptor-1 in acute mountain sickness. Journal of applied physiology 9816261629
  59. 59. Tissot van PatotM.C., Gassman, M. 2011Hypoxia: Adapting to High Altitude by Mutating EPAS-1, the Gene Encoding HIF-2. High altitude medicine and biology 12157167
  60. 60. TobyI. TChicoineL. GCuiHet al2010Hypoxia-induced proliferation of human pulmonary microvascular endothelial cells depends on epidermal growth factor receptor tyrosine kinase activation. American journal of physiology and lung cell molecular physiology 298:L-600L606.
  61. 61. TuderR. MVoelkelN. F2002Angiogenesis and pulmonary hypertension: A unique process in a unique disease. Antioxidants & Redox Signaling 4833843
  62. 62. VadivelAAbozaidSVan HaaftenTet al2010Adrenomedullin Promotes Lung Angiogenesis, Alveolar Development, and Repair. American Journal of Respiratory Cell and Molecular Biology.43152160
  63. 63. VásquezI. CHernándezA2012Hipertensión pulmonar en pollos, lapso de exposición a la hipoxia hipobárica y relación peso pulmonar: peso corporal, bajo condiciones de temperatura controlada. Revista Colombiana de Ciencias Pecuarias 258189
  64. 64. VoelkelN. FTuderR. M2000Hypoxia-induced pulmonary vascular remodelling: a model for what human disease?. Journal of Clinical Investigation 106733738
  65. 65. WagnerE:MPetracheISchofieldBMitznerW2006Pulmonary ischemia induces lung remodeling and angiogenesis. Journal of Applied Physiology 100587593
  66. 66. WeberCSchmittRBirnboeckHHoptgartnerGVan MarleS. PPeetersP. AJonkmanJ. HJonesC. R1996Pharmacokinetics and pharmacodynamics of the endothelin antagonist bosentan in healthy human subjects. Clin Pharmacol Ther 60124137
  67. 67. WidemanR. FHamalK. R2011Idiopathic Pulmonary Arterial Hypertension: An Avian Model for Plexogenic Arteriopathy and Serotonergic Vasoconstriction. Journal of Pharmacological and toxicological methods 63283295
  68. 68. WickstromS. AAlitaloKKeski-ojaJ2003Endostatin Associates with Lipid Rafts and Induces Reorganization of the Actin Cytoskeleton via Down-Regulation of RhoA Activity. Journal of Biological Chemistry 2783789537901
  69. 69. WulffCWilsonHDicksonS. Eet al2002Hemochorial placentation in the primate: expression of endothelial growth factor, angiopoietins, and their receptors throughout pregnancy. Biology of Reproduction 668028012
  70. 70. YoderM. C2011Progenitor Cells in the Pulmonary Circulation. Proceedings of the American Thoracic Society 20118466
  71. 71. YamamotoATakahashiHKojimaYet al2008Downregulation of Angiopoietin-1 and Tie2 in Chronic Hypoxic Pulmonary Hipertension. Respiration. 75328338

Written By

Aureliano Hernández and Rafael A. Areiza

Submitted: April 26th, 2012 Published: July 17th, 2013