ReviewCellular and molecular mechanisms of pulmonary vascular remodeling: role in the development of pulmonary hypertension
Section snippets
Introduction: hemodynamics of pulmonary hypertension and the concept of feedback between pulmonary arterial pressure and tissue remodeling
Human lungs constitute the only organ in the body that receives the entire cardiac output at all times. Such a tremendous capacity can be demanding and places the pulmonary circulation system in a position that is vulnerable to injury as a result of developmental or acquired disorders affecting the heart or lungs, as well as conditions that may also affect the systemic vasculature. The pulmonary circulation is normally a high-flow, low-resistance, low-pressure system that carries blood into the
Pulmonary arteries and veins
Pulmonary morphometry and modeling, that is, the study of the complex system of arteries, veins, and capillaries of the lung, has allowed for the extraction and extrapolation of hemodynamic data that is important in assessing pulmonary vascular disease. Fig. 1A shows a typical cast of a small segment of an arterial tree in the human lung. Three schemes have been proposed to describe the complex structure of the pulmonary circulation: the Weibel model, the Strahler model, and the
The physics of the pulmonary circulation
The laws of physics relate pulmonary hypertension to the changes in morphology and composition of the system, the mechanical properties of the tissues, the pumping of the heart, and the boundary conditions. Theoretical biomechanics has advanced to a degree such that a precise and detailed prediction can be made of the blood pressure and flow anywhere in the lung when the morphological, constitutive, and boundary conditions are known. It is a useful tool for the investigation of the molecular
Fundamental molecular and pathological derangements in idiopathic pulmonary artery hypertension (IPAH)
Pulmonary hypertension can occur in a variety of disease conditions including diseases in which pulmonary arteriopathy can be the primary disease (e.g., idiopathic pulmonary arterial hypertension) or diseases that can be present with pulmonary hypertension as a sequelae of other cardiopulmonary diseases, the so-called “secondary pulmonary hypertension (SPH).” The location of the vascular abnormality in any kind of pulmonary hypertension, either due to obstructive or obliterative process,
Pulmonary arterial vasoconstriction
Pulmonary vasoconstriction in general can be interpreted in one of two forms: (a) longitudinal constriction (vessel shortening) or (b) cross-sectional constriction (vessel narrowing). In vivo, the length of blood vessels within the lungs is generally considered somewhat fixed, while their diameters constantly change to accommodate the ever-changing physiological parameters and requirements. For the purposes of this article, vasoconstriction refers to an increase in tensile force which
Pulmonary arterial wall remodeling
Under normal conditions, the thickness and tissue mass of the pulmonary arterial walls are maintained at an optimal level by a fine balance between proliferation and apoptosis of fibroblasts, PASMC, and PAEC. If this balance is disturbed in favor of proliferation, the pulmonary arterial wall thickens, narrowing and eventually obliterating the vessel lumen, and leading to increased PVR (Fig. 8). This process also decreases pulmonary vascular compliance which accommodates for an increase in
Cellular and molecular mechanisms in the development of pulmonary hypertension
In addition to the synthetic, structural, and functional abnormalities in the pulmonary vasculature discussed above, substantial and convincing evidence has recently emerged that point to multiple derangements in complex intracellular signaling pathways that can contribute to the manifestation of IPAH within and between individuals affected by this disease or condition. It is now generally accepted that this condition involves a heterogeneous constellation of multiple genetic, molecular, and
Summary
To unravel the etiology of IPAH, numerous studies in the recent past have tackled its pathophysiology from many different angles. It is now clear that this is a disease entity that defies a single predominating pathophysiological cascade theory, but rather it involves a heterogeneous constellation of multiple genetic, molecular, and humoral abnormalities. Although each abnormality is likely important in itself, none appears to be sufficient to cause the disease by itself. Interestingly, some of
Acknowledgements
This work is supported in part by grants from the National Institutes of Health (HL 64945, HL 54043, HL 66012, HL 69758, HL 66941 and HL 43026). The authors would like to thank O. Platoshyn, S. Zhang, Y. Yu, I. Fantozzi, E.E. Brevnova, D. Ekhterae, S. Krick, B.R. Lapp, S.S. McDaniel, H. Kim, C.L. Bailey, M.A. Sweeney, J. Kriett, and P.A. Thistlethwaite for their contribution and assistance to this work.
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