Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) is a rare and debilitating disease characterized by increased pulmonary vascular resistance (PVR) and pressure overload of the right side of the heart, ultimately leading to death.¹ In PAH, vasculopathy has been identified in all the vessels of the pulmonary arterial circulation, and different lesions involved in increased PVR can affect different layers of the vascular walls.^1,2 The functional status of vessels involved in the pulmonary circulation as well as the PVR and pulmonary arterial pressures have a significant influence on the treatment of patients with PAH and their respective outcomes.²

Vascular remodeling can occur in vessels with varying diameters, including smaller precapillary arterioles with diameters of 20 μm to 70 μm and larger vessels with diameters up to 500 μm such as the distal arteries. Medial hypertrophy and hyperplasia can be found in the distal muscular arteries, as well as intimal and adventitial fibrosis. The development of plexiform lesions is also common and can contribute to impaired pulmonary and bronchial circulations. In the smaller vessels, muscularization, obliteration, and perivascular inflammation are commonly observed.¹

Intimal Remodeling and Plexiform Lesions

Lesions formed in the intimal endothelial layer of the vessels contribute significantly to the increase in PVR.² Changes in these vessels can be characterized by intimal thickening due to the accumulation of collagen, mucin-rich matrix, fibroblasts, endothelial cells, and pulmonary arterial smooth muscle cells (PASMCs).^1,2 

Plexiform lesions can also be associated with the intimal layer. These lesions are the histological hallmark of PAH and have a functional role in vascular remodeling as anastomotic structures between the pulmonary and bronchial circulations.¹ They are typically located at vascular branching points, containing vascular channels and resembling glomeruloid-like structures. The cells present in these structures are T-cells, monocytes, macrophages, and tryptase-positive mast cells.¹ Plexiform lesions are usually observed in the advanced stages of the disease, and they are more frequently associated with idiopathic PAH.^2-4 They can also occur in pulmonary hypertension associated with medical conditions such as HIV infection, liver cirrhosis, or congenital heart malformations.² 

Concentric lesions also have a significant impact in the increase in PVR. About 20% to 25% of pulmonary arteries with diameters ranging from 25 μm to 200 μm show defects on the intimal layer with occlusion or concentric lesions.² It has been suggested that this type of lesion can originate from remodeled plexiform lesions, however, lesions containing smooth muscle cells have been also identified.^5,6 

Medial Layer Remodeling

The medial vascular layer is mainly composed of PASMCs and can increase in thickness by about 20%, compromising PVR. The proliferation of PASMCs is the key player in this vascular remodeling.¹ Muscularized arteries and precapillary arterioles are the main vessels affected.² Although it typically occurs in mild to severe cases of pulmonary hypertension, research shows that the increase in thickness of the medial layer may also occur with individual exposure to cigarette smoke.⁷

Adventitial Layer Remodeling

The adventitial layer of the vessels is mainly formed by fibroblasts, containing also immunomodulatory cells, resident progenitor cells, endothelial cells of the vasa vasorum, and adrenergic nerves.⁸ The thickening of this layer is less commonly observed in PAH, and it can occur with no clear impact on the disease process.³ In idiopathic PAH, the thickness of the adventitial layer can increase by up to 28% of the arterial diameter. The deposition of collagen is the main reason for this increase.² Although the role of the adventitial layer in vascular remodeling is unclear, the structural changes occurring in this layer may function as an inflammatory signaling hub, promoting interactions between fibroblasts and macrophages and suggesting that changes in vascular thickness may not be solely responsible for promoting PAH development.¹ 

Perivascular Inflammation in PAH

Perivascular inflammation occurs more frequently in severe cases of pulmonary hypertension. It may also occur in patients with concomitant diseases such as HIV infection.² B-cells, T-cells, and macrophages are typically found in the intimal lesions. The presence of CD4^– and CD8^– cells with the subsequent expression of the CD45RO T-cell marker supports cellular activation.² Plasmacytoid dendritic cells may also contribute to PAH pathogenesis through the production of type-1 interferon.¹

References

1. Tobal R, Potjewijd J, van Empel VPM, et al. Vascular remodeling in pulmonary arterial hypertension: the potential involvement of innate and adaptive immunity. Front Med (Lausanne). 2021;8:806899. doi:10.3389/fmed.2021.806899

2.Tuder RM, Marecki JC, Richter A, Fijalkowska I, Flores S. Pathology of pulmonary hypertension. Clin Chest Med. 2007 Mar;28(1):23-42, vii. doi: 10.1016/j.ccm.2006.11.010

3. Stacher E, Graham BB, Hunt JM, et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186(3):261-272. doi:10.1164/rccm.201201-0164OC

4. Pietra GG, Capron F, Stewart S, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):25S-32S. doi:10.1016/j.jacc.2004.02.033

5. Cool CD, Stewart JS, Werahera P, et al. Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers: evidence for a dynamic and heterogeneous process of pulmonary endothelial cell growth. Am J Pathol. 1999;155(2):411-419. doi:10.1016/S0002-9440(10)65137-1

6. Atkinson C, Stewart S, Upton PD, et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation. 2002;105(14):1672-1678. doi:10.1161/01.cir.0000012754.72951.3d

7. Santos S, Peinado VI, Ramírez J, et al. Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD. Eur Respir J. 2002;19(4):632-638. doi:10.1183/09031936.02.00245902

8. Stenmark KR, Nozik-Grayck E, Gerasimovskaya E, et al. The adventitia: essential role in pulmonary vascular remodeling. Compr Physiol. 2011;1(1):141-161. doi:10.1002/cphy.c090017

Reviewed by Harshi Dhingra, MD, on 3/21/2022.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.