Elsevier

Progress in Cardiovascular Diseases

Volume 45, Issue 3, November–December 2002, Pages 173-202
Progress in Cardiovascular Diseases

Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension

https://doi.org/10.1053/pcad.2002.130041Get rights and content

Abstract

Clinical pulmonary hypertension is characterized by a sustained elevation in pulmonary arterial pressure. Pulmonary vascular remodeling involves structural changes in the normal architecture of the walls of pulmonary arteries. The process of vascular remodeling can occur as a primary response to injury, or stimulus such as hypoxia, within the resistance vessels of the lung. Alternatively, the changes seen in more proximal vessels may arise secondary to a sustained increase in intravascular pressure. To withstand the chronic increase in intraluminal pressure, the vessel wall becomes thickened and stronger. This “armouring” of the vessel wall with extra-smooth muscle and extracellular matrix leads to a decrease in lumen diameter and reduced capacity for vasodilatation. This maladaptive response results in increased pulmonary vascular resistance and consequently, sustained pulmonary hypertension. The process of pulmonary vascular remodeling involves all layers of the vessel wall and is complicated by the finding that cellular heterogeneity exists within the traditional compartments of the vascular wall: intima, media, and adventitia. In addition, the developmental stage of the organism greatly modifies the response of the pulmonary circulation to injury. This review focuses on the latest advances in our knowledge of these processes as they relate to specific forms of pulmonary hypertension and particularly in the light of recent genetic studies that have identified specific pathways involved in the pathogenesis of severe pulmonary hypertension. Copyright 2002, Elsevier Science (USA). All rights reserved.

Section snippets

Normal morphology of the pulmonary vasculature

One of the main functions of the normal pulmonary circulation is respiratory gas exchange. To fulfil this purpose efficiently, the pulmonary circulation is a low-pressure, high-flow system with a great capacity for recruitment of normally unperfused vessels. The walls of the pulmonary arteries are therefore relatively thin, in keeping with their low transmural pressure. The anatomy of pulmonary arteries alters in a systematic way from the central “conduit” arteries to the peripheral

The role of growth factors

Many factors must act in concert to orchestrate the process of pulmonary vascular remodeling. However, recent advances in our understanding of the pathogenesis of primary pulmonary hypertension at the genetic and molecular level have suggested that alterations in certain key pathways may play a central role in initiating disease or contribute to disease progression.

Cell cycle

One of the major targets for any proliferative or anti-proliferative stimuli is the cell cycle, a strategy used by the cell to duplicate its contents and hence divide. Various regulators control each of the 5 phases of the cell cycle. Complexes of cyclins and cyclin-dependent kinases (cdk) are positive regulators, and their successive activation allows progression through each phase of the cycle resulting in cell replication. However, progression of the cell cycle can be inhibited by

Mechanisms regulating pulmonary vascular apoptosis

Apoptosis, or programmed cell death, is an important physiologic process regulating the homeostasis of cells. Thus, either excessive or limited apoptosis can lead to the development of a variety of diseases including pulmonary hypertension. The mechanisms of programmed cell death are complex, occurring through multiple independent pathways, and vary depending on cell type (reviewed in references 287 to 289). However, there are a number of common factors/mediators involved, and alterations in

Summary

Recent years have seen great progress in our understanding of the molecular and cellular mechanisms, which contribute to the maintenance of the normal pulmonary circulation and to the pathologic changes associated with pulmonary hypertension. These advances have come both from the identification of specific genes and from careful hypothesis-driven examination of regulatory pathways. On the one hand, this research has highlighted the enormous complexity of the biological systems that regulate

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    Address reprint requests to Nicholas W. Morrell, MD FRCP, Respiratory Medicine Unit, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.

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