Adding complexity to plexogenic arteriopathy

Abstract

@ERSpublicationsIn PAH, a wide range of abnormal pulmonary vascular manifestations exist, all arising from the endothelium http://ow.ly/IWH2305bXpQIn a landmark paper in the field of pulmonary hypertension research, Donald Heath and Jesse Edwards, in 1958, described the pulmonary vascular pathology that accompanies severe forms of pulmonary hypertension [1]. Examining lung tissue samples from patients with pulmonary hypertension associated with congenital heart disease and patients with primary pulmonary hypertension (now called idiopathic pulmonary arterial hypertension (PAH)), they distinguished six grades of severity and introduced the term "plexiform lesions". Ever since, the plexiform lesions have been a subject of interest and of frequently contentious debates [2][3][4][5]. To touch on just a few of the unresolved issues and questions: why do these lesions form? How many of these lesions are present in a patient's lung and are they haemodynamically important? What are the cellular components and the cell(s) of origin? A few investigators continue to be bored by these questions and have concluded that these complex vascular lesions are important mostly as an entertainment to a handful of pathologists.We believe that these signature lesions of severe forms of PAH are indeed very interesting. Firstly, they are unique to the lung and they can teach us about fundamental principles of vascular biology; for example, the first "law" of vascular biology that the endothelium must be a monolayer [6]. In the plexiform lesions, endothelial cells pile up and the law of the monolayer is broken. This fact opened the gates to further research that has led to the formulation of pathobiological hypotheses and concepts such as endothelial cell injury giving rise to the proliferation of apoptosis-resistant, phenotypically altered, lumen-obliterating cells: "misguided angiogenesis" and "wound healing gone awry" [7]. Indeed, these complex vascular lesions have taught us many lessons and their investigation has greatly enriched our knowledge of the spectrum of cellular responses of the lung circulation to chronic stress. Secondly, plexiform lesions are a hallmark of irreversible and generally very difficult to treat pulmonary vascular syndromes. This is certainly true in PAH and perhaps also in chronic thromboembolic pulmonary hypertension (CTEPH), where some authors have reported that the presence of plexiform lesions is associated with pulmonary hypertension that persists after thromboendarteriectomy [8] (while others have argued that plexiform lesions do not exist in CTEPH [9]). Thirdly, the concept that lumen-obliterating lesions, other than plexiform lesions, are indeed haemodynamically important has led to the search for animal models that present such lesions and are irresponsive to vasodilator treatment. These models are "two hit" models; for example, monocrotaline, the endothelial cell toxic alkaloid, plus high shear stress induced by pneumonectomy as described by OKADA et al. [10], or the combination of the vascular end...

A pro-con debate: current controversies in PAH pathogenesis at the American Thoracic Society International Conference in 2017

“…In an intriguing recent report, Abman's group (29) has suggested that the plexiform lesions may not even arise in the pulmonary circulation at all but in the bronchial circulation, as a result of the opening of intrapulmonary bronchial anastomoses in response to increased pulmonary arterial pressures overloading the bronchial venous bed. This concept is further supported by a report that patients harboring BMPR2 mutations exhibit more marked bronchial arterial remodeling and angiogenesis and are more prone to hemoptysis than patients without these mutations (118). Patients with BMPR2 mutations are known to exhibit a more severe PAH phenotype, present earlier, and have a worse prognosis than those with idiopathic disease (27), consistent with a possible relationship between severity of hemodynamic abnormalities and remodeling within the bronchial venous bed.…”

O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension

“…These complex vascular formations originate from the remodeled pulmonary arterial lumen and small precapillary arteries and contain endothelial as well as smooth muscle cells that express many angiogenic factors [7,48]. Furthermore, the molecular signals responsible for angiogenesis within the plexiform lesions have been thought to be a continuous process involving the formation of new blood vessels from pre-existing blood vessels driven by their dysregulated molecular make-up (e.g., altered VEGF signaling) called "misguided angiogenesis," a term given by Tuder and Voelkel [13,15,[49][50][51][52] owever, the development and overall significance of the plexiform lesion are not yet fully understood. It has been generally thought that the angiogenic processes that coordinate the vascular remodeling and dysfunction in PAH are solely determined by genetic cues, but many recent reports have shown that dysregulated metabolism may be involved [51][52][53].…”

Dysregulated VEGF/VEGFR-2 Signaling and Plexogenic Lesions in the Embryonic Lungs of Chickens Predisposed to Pulmonary Arterial Hypertension

“…The clinical manifestations of PAH may include symptoms such as dyspnea, fatigue, chest discomfort, cyanosis, and lower extremity swelling. At the histological level, severe PAH is marked by the presence of the so-called plexiform lesions, occlusive, glomeruloid-like vascular structures typically occurring distal to branch points of small pulmonary arteries [3,4]. These structures have been identified in individuals across various age groups [3,5], and the earliest occurrence of the lesions has been documented during in utero stages, exemplified by a case involving a 31-week stillborn fetus with premature closure of the ductus arteriosus and lung hypoplasia [6].…”