Pathogenic mechanisms of pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) 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.

Figure 1. Pulmonary Arterial Pathobiology Involves the Coordinate Action of Multiple Cell Types

The histologic progression of the pulmonary vasculature from quiescence to pathogenic activation in PAH involves numerous vascular cell types and phenotypic responses. Initial injury to the endothelium and/or adventitial fibroblasts may activate pathogenic signaling pathways. These result in an imbalance of secreted vascular effectors that drive the vascular responses of vasoconstriction, proliferation, and dysregulation of apoptosis, leading to the formation of a layer of “neointima” (red arrow) and, in some cases, plexiform lesions. Activation of platelets (blue thrombus) and extravasation/migration of blood-borne inflammatory cells (green arrow) likely play prominent roles in these processes, but their exact mechanistic actions are unclear. Engraftment and differentiation of vascular progenitor cells may influence disease progression (purple arrow). Transdifferentiation of endothelial cells to vascular smooth muscle cells may contribute as well (blue arrow). Micrographs of pulmonary arteries are courtesy of www.scleroderma.org and Humbert et al., Treatment of Pulmonary Arterial Hypertension, New England Journal of Medicine, 2004, 351(14):1425-1436; Copyright 2004, Massachusetts Medical Society. All rights reserved.

Figure 2. Common Mechanisms Promoting PAH May Rely upon the Intersecting BMPR-II and Serotoninergic Pathways

In the serotoninergic pathway, both genetic predisposition (i.e., platelet storage pool disease, perhaps 5-HT2B mutations, or perhaps the L-allele variant of 5-HTT) and specific exogenous stimuli (i.e., hypoxia, anorexigens) lead to vessel remodeling via increased serotonin levels, increased 5-HTT activity, and/or increased serotonin receptor signaling. In the BMPR-II pathway, genetic predisposition (such as heterozygous loss-of-function +/− BMPR2 mutations) and, perhaps, exogenous stimuli lead to decreased receptor expression, alteration of downstream signaling, and resulting vessel remodeling. Additional pathogenic mechanisms may upregulate the angiopoietin-1/Tie2 receptor pathway with resulting repression of BMPR-1A function and alteration of BMPR-II signaling. Interestingly, serotonin can directly upregulate angiopoietin-1 and can modulate downstream Smad function, thereby influencing the BMP signaling cascade. This functional intersection has yet to be fully described, but may represent a common, unifying mechanism of pathogenesis.

Figure 3. Physiologic/Exogenous Triggers of Pulmonary Arterial Hypertension Are Poorly Understood at the Molecular Level

While most of these clinical risk factors have been known for years, the mechanisms that lead to the imbalance of vascular mediators and dysregulated cellular phenotypes are unclear.

Figure 4. Paradigm for the “Multiple-Hit” Hypothesis Promoting Pulmonary Arterial Hypertension

Susceptible persons with genetic or acquired traits do not progress to PAH without suffering from additional insults that are synergistic in the pathogenesis of disease.