The adventitia: Essential role in pulmonary vascular remodeling

Abstract

A rapidly emerging concept is that the vascular adventitia acts as a biological processing center for the retrieval, integration, storage, and release of key regulators of vessel wall function. It is the most complex compartment of the vessel wall and comprises a variety of cells including fibroblasts, immunomodulatory cells, resident progenitor cells, vasa vasorum endothelial cells, and adrenergic nerves. In response to vascular stress or injury, resident adventitial cells are often the first to be activated and reprogrammed to then influence tone and structure of the vessel wall. Experimental data indicate that the adventitial fibroblast, the most abundant cellular constituent of adventitia, is a critical regulator of vascular wall function. In response to vascular stresses such as overdistension, hypoxia, or infection, the adventitial fibroblast is activated and undergoes phenotypic changes that include proliferation, differentiation, and production of extracellular matrix proteins and adhesion molecules, release of reactive oxygen species, chemokines, cytokines, growth factors, and metalloproteinases that, collectively, affect medial smooth muscle cell tone and growth directly and that stimulate recruitment and retention of circulating inflammatory and progenitor cells to the vessel wall. Resident dendritic cells also participate in "sensing" vascular stress and actively communicate with fibroblasts and progenitor cells to simulate repair processes that involve expansion of the vasa vasorum, which acts as a conduit for further delivery of inflammatory/progenitor cells. This review presents the current evidence demonstrating that the adventitia acts as a key regulator of pulmonary vascular wall function and structure from the "outside in."

Figure 1

Complex cellular composition of the vascular adventitia. Unlike the normal intima and media, which are composed of endothelial and smooth muscle cells, respectively, the normal adventitia comprises a wide variety of cell types, including fibroblasts, resident progenitor cells, immunomodulatory cells (dendritic cells, macrophages, T lymphocytes), vasa vasorum endothelial cells, and adrenergic nerves.

Figure 2

Fibroblasts play a central role in the control of vascular function. Fibroblasts produce and organize elements of extracellular matrix (ECM) and also degrade structural elements of the ECM; they secrete a complex mixture of growth factors, cytokines, chemokines; they communicate with neural cells with cells of hematopoietic origin (dendritic cells, macrophages, T lymphocytes), with SMCs and endothelial and epithelial cells; importantly, this communication is reciprocal. Abbreviations: MMP, matrix metalloproteinase; TIMP, tissue inhibitor of matrix metalloproteinases. Adapted from reference .

Figure 3

Multiple origins for myofibroblasts in the vasculature: α-SM-actin-expressing myofibroblasts are believed to originate via: (i) differentiation of tissue resident fibroblasts, (ii) de-differentiation of resident smooth muscle cell (SMC), (iii) epithelial-to-mesenchymal trans-differentiation (EMT), (iv) endothelial-to-mesenchymal transition (EnMT), (v) differentiation of resident or bone marrow-derived circulating progenitor cells. Adapted from Hinz B, et al. The myofibroblast: one function, multiple origins. Am J Pathol 170(6): 1807–1816, 2007.

Figure 4

Essential role of the adventitial fibroblast in initiating and perpetuating vascular inflammation and, consequently, vascular remodeling. In response to hormonal, infectious, or environmental (hypoxia, hemodynamic stress, etc.) stimuli, the fibroblast is activated and secretes chemokines, cytokines, and matricellular proteins involved in the recruitment of monocytes, lymphocytes, and progenitor cells. With time, fibroblasts upregulate adhesion molecule expression, which promotes retention of leukocytes and progenitor cells within the adventitia. Some of the newly recruited cells can differentiate into fibroblasts and myofibroblasts, which perpetuate the cycle, thus leading to persistent inflammation and structural vascular remodeling. Abbreviation: PA, pulmonary artery.

Figure 5

(A–E), Angiogenic expansion of the vasa vasorum in the pulmonary artery adventitia of calves with severe hypoxia-induced pulmonary hypertension. Histopathology of large (A, C) and small (B, D) pulmonary arteries. Both histological, H&E (A, B) and immunofluorescent, PECAM-1/CD31 (C, D) stainings demonstrate marked expansion of the vasa vasorum capillary network in adventitial, perivascular regions. Quantitative morphometric analyses demonstrated that the volume density (V_V) of vasa vasorum is significantly greater in neonatal calves with severe hypoxia-induced pulmonary hypertension compared with normoxic controls (E). (F, G) Angiogenic responses in the adventitia of a human patient with pulmonary fibrosis and associated pulmonary hypertension. Medium sized pulmonary artery stained with CD31, demonstrating evidence for capillary network expansion in the perivascular area (medial/adventitial region, arrow) (F). CD31 immunohistochemical evidence of capillary proliferation (arrow) (G). Bars, 500 μm in A and C, 100 μm in B, D, F, and 25 μm in G.