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Pulmonary Vascular Disease Related to Hemodynamic Stress in the Pulmonary Circulation

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Abstract

Hemodynamic stress in the pulmonary vessel is directly linked to the development of vascular remodeling and dysfunction, ultimately leading to pulmonary hypertension. Recently, some advances have been made in our molecular understanding of the exogenous upstream stimuli that initiate hemodynamic pertubations as well as the downstream vasoactive effectors that control these responses. However, much still remains unknown regarding how these complex signaling pathways connect in order to result in these characteristic pathophysiological changes. This chapter will describe our current understanding of and needed areas of research into the clinical, physiological, and molecular changes associated with pressure/volume overload in the pulmonary circulation. © 2011 American Physiological Society. Compr Physiol 1:123‐139, 2011.

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Figure 1. Figure 1.

Pulmonary hypertension (PH) involves the coordinated action of multiple endothelial‐derived vascular effectors. The histological progression of the pulmonary vasculature from quiescence to pathogenic activation and vasoconstriction in PH in large part involves the dysregulation of endothelial function. Initial injury to the endothelium may initiate pathogenic signaling pathways. These pathways activate an imbalance of secreted vascular mediators that drive the vascular responses of vasoconstriction, proliferation, thrombosis, and dysregulation of apoptosis, leading to the formation of a layer of “neointima.” Pathological phenotypes that may influence disease progression include vessel inflammation, transdifferentiation of endothelial cells to vascular smooth muscle cells (VSMCs), and transdifferentiation of fibroblasts and VSMCs to myofibroblasts. Engraftment and differentiation of vascular progenitor cells may contribute, as well.

This figure is reproduced with modifications from reference , with permission from Elsevier Limited. Micrographs of pulmonary arteries courtesy of and Humbert et al., Treatment of pulmonary arterial hypertension. N Engl J Med 351(14): 1425‐1436, 2004
Figure 2. Figure 2.

The pulmonary vascular endothelium is integral for sensing and responding to hemodynamic stress. The pulmonary vascular endothelial cell acts as a sensor of physiological and pathophysiological conditions, transmitted primarily in the forms of mechanical or hemodynamic stimuli as well as humoral, neural, and hypoxic triggers. In response, endothelial cells produce and secrete a tightly regulated balance of vasoactive effectors in the vascular milieu. These effectors can then act in an autocrine fashion to autoregulate endothelial function or, in a paracrine fashion, to mediate contractile, secretory, or proliferative function of neighboring vascular smooth muscle cells.

Figure 3. Figure 3.

Common mechanisms promoting pulmonary hypertension due to hemodynamic stress may rely upon the intersecting BMPR‐II and serotoninergic pathways. In the serotoninergic pathway, both genetic predisposition and specific exogenous stimuli lead to vessel remodeling via increased serotonin levels and signaling activity. 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. The precise details of how hemodynamic stressors regulate these pathways are under investigation.

This figure is reproduced with modifications from reference
Figure 4. Figure 4.

Paradigm for the “multiple‐hit” hypothesis promoting PH secondary to pressure/volume overload. Hemodynamic stress induces PH with histopathological complications in most, if not all, persons when subjected to pressure or volume overload chronically. However, susceptible persons with genetic or acquired traits may progress to pulmonary hypertension more rapidly or to a heightened extent. These factors appear synergistic in the pathogenesis of disease, leading to a common set of end‐stage pathologies.



Figure 1.

Pulmonary hypertension (PH) involves the coordinated action of multiple endothelial‐derived vascular effectors. The histological progression of the pulmonary vasculature from quiescence to pathogenic activation and vasoconstriction in PH in large part involves the dysregulation of endothelial function. Initial injury to the endothelium may initiate pathogenic signaling pathways. These pathways activate an imbalance of secreted vascular mediators that drive the vascular responses of vasoconstriction, proliferation, thrombosis, and dysregulation of apoptosis, leading to the formation of a layer of “neointima.” Pathological phenotypes that may influence disease progression include vessel inflammation, transdifferentiation of endothelial cells to vascular smooth muscle cells (VSMCs), and transdifferentiation of fibroblasts and VSMCs to myofibroblasts. Engraftment and differentiation of vascular progenitor cells may contribute, as well.

This figure is reproduced with modifications from reference , with permission from Elsevier Limited. Micrographs of pulmonary arteries courtesy of and Humbert et al., Treatment of pulmonary arterial hypertension. N Engl J Med 351(14): 1425‐1436, 2004


Figure 2.

The pulmonary vascular endothelium is integral for sensing and responding to hemodynamic stress. The pulmonary vascular endothelial cell acts as a sensor of physiological and pathophysiological conditions, transmitted primarily in the forms of mechanical or hemodynamic stimuli as well as humoral, neural, and hypoxic triggers. In response, endothelial cells produce and secrete a tightly regulated balance of vasoactive effectors in the vascular milieu. These effectors can then act in an autocrine fashion to autoregulate endothelial function or, in a paracrine fashion, to mediate contractile, secretory, or proliferative function of neighboring vascular smooth muscle cells.



Figure 3.

Common mechanisms promoting pulmonary hypertension due to hemodynamic stress may rely upon the intersecting BMPR‐II and serotoninergic pathways. In the serotoninergic pathway, both genetic predisposition and specific exogenous stimuli lead to vessel remodeling via increased serotonin levels and signaling activity. 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. The precise details of how hemodynamic stressors regulate these pathways are under investigation.

This figure is reproduced with modifications from reference


Figure 4.

Paradigm for the “multiple‐hit” hypothesis promoting PH secondary to pressure/volume overload. Hemodynamic stress induces PH with histopathological complications in most, if not all, persons when subjected to pressure or volume overload chronically. However, susceptible persons with genetic or acquired traits may progress to pulmonary hypertension more rapidly or to a heightened extent. These factors appear synergistic in the pathogenesis of disease, leading to a common set of end‐stage pathologies.

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Stephen Y Chan, Joseph Loscalzo. Pulmonary Vascular Disease Related to Hemodynamic Stress in the Pulmonary Circulation. Compr Physiol 2010, 1: 123-139. doi: 10.1002/cphy.c090004