Expression of angiogenesis‐related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis

Tuder, Rubin M.; Chacon, Mati; Alger, Lori; Wang, Jun; Taraseviciene‐Stewart, Laimute; Kasahara, Yasunori; Bishop, Anne E.; Geraci, Mark W.; Semenza, Gregg L.; Yacoub, Magdi; Polak, Julia M.; Voelkel, Norbert F.

doi:10.1002/path.953.abs

Cited by 87 publications

(113 citation statements)

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“…In severe pulmonary arterial hypertension (PAH), there is a unique and characteristic presence of plexiform lesions in the lumens of medium and small precapillary pulmonary arteries. These lesions show enhanced expression of VEGF, VEGF receptor, HIF-1α, and HIF-1β, which suggests that lesions may develop by a process of disordered angiogenesis [54]. Similar results were recently obtained with cultured endothelial cells isolated form patients with IPAH.…”

Section: Hypoxia Signaling In the Lungsupporting

confidence: 83%

Hypoxia and chronic lung disease

et al. 2007

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The lung is both the conduit for oxygen uptake and is also affected by hypoxia and hypoxia signaling. Decreased ventilatory drive, airway obstructive processes, intra-alveolar exudates, septal thickening by edema, inflammation, fibrosis, or damage to alveolar capillaries will all interpose a significant and potentially life-threatening barrier to proper oxygenation, therefore enhancing the alveolar/arterial pO 2 gradient. These processes result in decreased blood and tissue oxygenation. This review addresses the relationship of hypoxia with lung development and with lung diseases. We particularly focus on molecular mechanisms underlying hypoxia-driven physiological and pathophysiological lung processes, specifically in the infant lung, pulmonary hypertension, and chronic obstructive pulmonary disease.Keywords Hypoxia . Lung . Pathology . HIF Air, containing oxygen at approximately 21% partial pressure at sea level (140-150 mmHg), travels through up to 20 generations of airways by mass flow and then diffuses into the gas exchange units (alveoli) in the lung with a partial pressure of approximately 105-110 mmHg. The human lung contains approximately 480 million alveoli, which represent 64% of total lung structure. These alveoli are elegantly packed in only 1.3-2.6 L of total lung volume, providing a surface area of 120-150 m 2 , equivalent to the dimensions of a "tennis court" dedicated for gas exchange. Although the molecular determinants of lung size are not known, oxygen diffusion constant and gas exchange surface area are roughly proportional to body weight and oxygen consumption in different species [1]. Physical hyperactivity and exposure to a cold environment or high altitude lead to increased oxygen diffusion capacity, in proportion to enhanced oxygen consumption [1].Decreased ventilatory drive, airway obstructive processes, intraalveolar exudates, septal thickening by edema, inflammation, fibrosis, or damage to alveolar capillaries will all interpose a significant and potentially life-threatening barrier to proper oxygenation, therefore enhancing the alveolar/ arterial pO 2 gradient. This review addresses the contribution of hypoxia to lung diseases and the potential molecular mechanisms involved in hypoxia-driven physiological and pathophysiological lung processes (Fig. 1), particularly in the infant lung, pulmonary hypertension, and chronic obstructive pulmonary disease. The fundamental concepts underlying hypoxia-induced gene expression and the molecular regulation of HIF(s) also apply to the lung, and they will be cited in relation to their demonstrated role in lung physiology or pathophysiology.

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Section: Hypoxia Signaling In the Lungsupporting

confidence: 83%

Hypoxia and chronic lung disease

et al. 2007

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“…VEGF and its receptors play a key role during embryonic vasculogenesis and also during normal and pathological angiogenesis. Increased expression of VEGF and its receptor VEGF-R2 has been reported in plexiform lesions in the lungs of patients with idiopathic PAH and PAH secondary to CHD (38,46,127). Interestingly, similar to human plexiform lesions, increased expression of VEGF and VEGF-R2 has been reported in the complex lesions found in the VEGF-R2 blocker ϩ hypoxia model of severe PH.…”

Section: Caveolin-1 and Plexiform Lesionsmentioning

confidence: 67%

“…It consists of elastic fragmentation and plexus of small vessels within an artery. However, arteries with dilatation lesions that show dilated segments with degenerative changes in SMCs did not develop plexiform lesions (127)(128)(129). Furthermore, the hypoxia-induced PH is reversible upon removal of hypoxic condition (17,118).…”

Section: Perturbation Of Ec Membranementioning

confidence: 95%

Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity

Mathew

2014

American Journal of Physiology-Heart and Circulatory Physiology

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Mathew R. Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity. Am J Physiol Heart Circ Physiol 306: H15-H25, 2014. First published October 25, 2013 doi:10.1152/ajpheart.00266.2013.-Pulmonary hypertension (PH) is a progressive disease with a high morbidity and mortality rate. Despite important advances in the field, the precise mechanisms leading to PH are not yet understood. Main features of PH are loss of vasodilatory response, the activation of proliferative and antiapoptotic pathways leading to pulmonary vascular remodeling and obstruction, elevated pressure and right ventricular hypertrophy, resulting in right ventricular failure and death. Experimental studies suggest that endothelial dysfunction may be the key underlying feature in PH. Caveolin-1, a major protein constituent of caveolae, interacts with several signaling molecules including the ones implicated in PH and modulates them. Disruption and progressive loss of endothelial caveolin-1 with reciprocal activation of proliferative pathways occur before the onset of PH, and the rescue of caveolin-1 inhibits proliferative pathways and attenuates PH. Extensive endothelial damage/loss occurs during the progression of the disease with subsequent enhanced expression of caveolin-1 in smooth muscle cells. This caveolin-1 in smooth muscle cells switches from being an antiproliferative factor to a proproliferative one and participates in cell proliferation and cell migration, possibly leading to irreversible PH. In contrast, the disruption of endothelial caveolin-1 is not observed in the hypoxia-induced PH, a reversible form of PH. However, proliferative pathways are activated in this model, indicating caveolin-1 dysfunction. Thus disruption or dysfunction of endothelial caveolin-1 leads to PH, and the status of caveolin-1 may determine the reversibility versus irreversibility of PH. This article reviews the role of caveolin-1 and cell membrane integrity in the pathogenesis and progression of PH.caveolin-1; endothelial cells; pulmonary hypertension; smooth muscle cells THIS ARTICLE is part of a collection on Pathophysiology of Hypertension. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology.org/.In 1891, Ernst von Romberg, a German physician, described histological changes in pulmonary hypertension (PH) as pulmonary vascular sclerosis (30). Since then remarkable advances have been made in the understanding of PH, but the pathogenesis of PH still remains elusive, partly because a number of diseases can lead to PH and multiple signaling pathways are implicated in PH. Furthermore, not all signaling pathways are activated in a given patient, and their activation may depend on the stage of the disease. Experimental data suggest that the vascular changes occur before the onset of PH (47,48). Therefore, it is not surprising that by the time the diagnosis of PH is made, most patients have significant pathological changes in pulmonary vasculatu...

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“…We have proposed that plexiform lesions represent a process of misguided angiogenesis based on the findings of expression of vascular endothelial growth factor (VEGF), its receptors 1 (flt) and 2(kdr), and hypoxia inducible factor (HIF)-1α and β [22]. The finding of monoclonality of endothelial cells in plexiform lesions in IPAH, but not in similar lesions in PH associated with congenital heart malformation, suggests that these lesions might arise from mutations in tumor suppressor genes [23].…”

Section: Pathobiologymentioning

confidence: 99%

“…VEGF [22], endothelin-1 [32], and survivin [33;34] are among the factors present in plexiform lesions that may enhance endothelial cell and smooth muscle cell proliferation or decrease vascular cell apoptosis. These lesions have decreased expression of anti-remodeling mediators such as nitric oxide synthase [35] and prostacyclin synthase [36], and tumor suppressors, such as caveolin-1 [37].…”

Section: Pathobiologymentioning

confidence: 99%