Elsevier

Microvascular Research

Volume 68, Issue 2, September 2004, Pages 75-103
Microvascular Research

Review
Cellular and molecular mechanisms of pulmonary vascular remodeling: role in the development of pulmonary hypertension

https://doi.org/10.1016/j.mvr.2004.06.001Get rights and content

Abstract

Pulmonary artery vasoconstriction and vascular remodeling greatly contribute to a sustained elevation of pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) in patients with pulmonary arterial hypertension (PAH). The development of PAH involves a complex and heterogeneous constellation of multiple genetic, molecular, and humoral abnormalities, which interact in a complicated manner, presenting a final manifestation of vascular remodeling in which fibroblasts, smooth muscle and endothelial cells, and platelets all play a role. Vascular remodeling is characterized largely by medial hypertrophy due to enhanced vascular smooth muscle cell proliferation or attenuated apoptosis and to endothelial cell over-proliferation, which can result in lumen obliteration. In addition to other factors, cytoplasmic Ca2+ in particular seems to play a central role as it is involved in both the generation of force through its effects on the contractile machinery, and the initiation and propagation of cell proliferation via its effects on transcription factors, mitogens, and cell cycle components. This review focuses on the role played by cellular factors, circulating factors, and genetic molecular signaling factors that promote a proliferative, antiapoptotic, and vasoconstrictive physiological milieu leading to vascular remodeling.

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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