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; Cool, Carlyne D.; Bishop, Anne E.; Geraci, Mark W.; Semenza, Gregg L.; Yacoub, Magdi H.; Polak, Julia M.; Voelkel, Norbert F.

doi:10.1002/path.953

Cited by 432 publications

(280 citation statements)

References 41 publications

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“…While our data establish that HIF-2␣ is the critical HIF-␣ homolog regulating pulmonary vascular responses, increased HIF-1␣ expression has been observed in PA-derived medial smooth muscle cells and within human plexiform lesions, a morphological hallmark of idiopathic pulmonary arterial hypertension (IPAH), suggesting that HIF1-dependent signaling may contribute to IPAH-associated proliferative vasculopathy (44). In mice, global heterozygous Hif1a deficiency dampened pulmonary vascular responses induced by prolonged hypoxia, a finding that suggested a role for HIF-1 in the pathogenesis of hypoxia-induced pulmonary hypertension.…”

Section: Discussionmentioning

confidence: 99%

The Endothelial Prolyl-4-Hydroxylase Domain 2/Hypoxia-Inducible Factor 2 Axis Regulates Pulmonary Artery Pressure in Mice

Kapitsinou

Rajendran

Astleford

et al. 2016

Molecular and Cellular Biology

114

138

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f Hypoxia-inducible factors 1 and 2 (HIF-1 and -2) control oxygen supply to tissues by regulating erythropoiesis, angiogenesis and vascular homeostasis. HIFs are regulated in response to oxygen availability by prolyl-4-hydroxylase domain (PHD) proteins, with PHD2 being the main oxygen sensor that controls HIF activity under normoxia. In this study, we used a genetic approach to investigate the endothelial PHD2/HIF axis in the regulation of vascular function. We found that inactivation of Phd2 in endothelial cells specifically resulted in severe pulmonary hypertension (ϳ118% increase in right ventricular systolic pressure) but not polycythemia and was associated with abnormal muscularization of peripheral pulmonary arteries and right ventricular hypertrophy. Concurrent inactivation of either Hif1a or Hif2a in endothelial cell-specific Phd2 mutants demonstrated that the development of pulmonary hypertension was dependent on HIF-2␣ but not HIF-1␣. Furthermore, endothelial HIF-2␣ was required for the development of increased pulmonary artery pressures in a model of pulmonary hypertension induced by chronic hypoxia. We propose that these HIF-2-dependent effects are partially due to increased expression of vasoconstrictor molecule endothelin 1 and a concomitant decrease in vasodilatory apelin receptor signaling. Taken together, our data identify endothelial HIF-2 as a key transcription factor in the pathogenesis of pulmonary hypertension.

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Section: Discussionmentioning

confidence: 99%

The Endothelial Prolyl-4-Hydroxylase Domain 2/Hypoxia-Inducible Factor 2 Axis Regulates Pulmonary Artery Pressure in Mice

Kapitsinou

Rajendran

Astleford

et al. 2016

Molecular and Cellular Biology

114

138

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“…Production of VEGF and its receptors is upregulated in human pulmonary tissue in both acute and chronic hypoxia [159]. Increased VEGF expression has also been observed in PAH, accompanied by elevated levels of VEGFR-1 in the affected pulmonary endothelium and specifically elevated levels of VEGFR-2 in plexiform lesions [6,160]; however, other signaling molecules that are typically involved in the VEGF angiogenic signaling cascade appear to decrease: phosphoinositide-3-kinase, Akt, and Src. As a result, a dysregulated response to VEGF has been proposed to critically influence endothelial cell survival, proliferation, and apoptosis.…”

Section: Vascular Effectorsmentioning

confidence: 99%

Pathogenic mechanisms of pulmonary arterial hypertension

Chan¹,

Loscalzo²

2008

Journal of Molecular and Cellular Cardiology

228

179

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Pulmonary arterial hypertension (PAH)1 is a complex disease that causes significant morbidity and mortality and is clinically characterized by an increase in pulmonary vascular resistance. The histopathology is marked by vascular proliferation/fibrosis, remodeling, and vessel obstruction. Development of PAH involves the complex interaction of multiple vascular effectors at all anatomic levels of the arterial wall. Subsequent vasoconstriction, thrombosis, and inflammation ensue, leading to vessel wall remodeling and cellular hyperproliferation as the hallmarks of severe disease. These processes are influenced by genetic predisposition as well as diverse endogenous and exogenous stimuli. Recent studies have provided a glimpse at certain molecular pathways that contribute to pathogenesis; these have led to the identification of attractive targets for therapeutic intervention. We will review our current understanding of the mechanistic underpinnings of the genetic and exogenous/acquired triggers of PAH. The resulting imbalance of vascular effectors provoking pathogenic vascular changes will also be discussed, with an emphasis on common and overarching regulatory pathways that may relate to the primary triggers of disease. The current conceptual framework should allow for future studies to refine our understanding of the molecular pathogenesis of PAH and improve the therapeutic regimen for this disease.

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“…Tuder et al [40] demonstrated immunohistochemically and via in situ hybridization that the EC in the plexiform lesions, not in the normal vasculature, express mRNA and protein for VEGF (the survival factor for EC) and VEGFR-2, thus suggesting that the formation of these lesions in PAH involves a process of disordered angiogenesis. Moreover, in PAH, the population of lung EC expands in a monoclonal pattern [41], and these EC contain an inactivating mutation of the transforming growth factor receptor II [42].…”

Section: The Su5416 Model and Classical Rodent Models Of Pahmentioning

confidence: 99%

The Effects of Antiangiogenic Compound SU5416 in a Rat Model of Pulmonary Arterial Hypertension

Sakao

2010

Respiration

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Several lines of evidence indicate that vascular endothelial growth factor (VEGF) plays a prosurvival and antiapoptotic role in endothelial cells. SU5416 is the first VEGF receptor 2 inhibitor to enter clinical development for cancer therapy. A phase I/II study of SU5416 has been completed, and the results show that SU5416 is well tolerated in patients with terminal cancers. It has been shown that VEGF receptor blockade using SU5416 combined with chronic hypoxia results in severe angioproliferative pulmonary hypertension (PAH) with neointimal changes in adult rats. Although classic animal models of pulmonary hypertension (that is, the monocrotaline and hypoxic models) do not form obstructive intimal lesions in the peripheral pulmonary arteries, the SU5416 model has shown pulmonary arterial changes resembling plexiform lesions. Therefore, the SU5416 model of PAH has been used for some time, and it has thus contributed to a better understanding of the pulmonary hypertensive process. However, the mechanism by which SU5416 combined with chronic hypoxia can result in PAH with plexiform-like lesions in adult rats is complex and still remains to be fully elucidated. The most likely explanation is that there is increased apoptosis of endothelial cells in response to the loss of the survival signaling, creating conditions favoring the emergence of apoptosis-resistant cells with increased growth potential, that is, the endothelial cell hyperproliferation that might characterize the plexiform lesions of human PAH. The aim of the present review is to provide information useful for understanding a potent inhibitor of VEGF receptor tyrosine kinase, SU5416, and to better understand its use for generating animal models of PAH.

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

Cited by 432 publications

References 41 publications

The Endothelial Prolyl-4-Hydroxylase Domain 2/Hypoxia-Inducible Factor 2 Axis Regulates Pulmonary Artery Pressure in Mice

The Endothelial Prolyl-4-Hydroxylase Domain 2/Hypoxia-Inducible Factor 2 Axis Regulates Pulmonary Artery Pressure in Mice

Pathogenic mechanisms of pulmonary arterial hypertension

The Effects of Antiangiogenic Compound SU5416 in a Rat Model of Pulmonary Arterial Hypertension

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