Selective expansion of fibroblast subpopulations from pulmonary artery adventitia in response to hypoxia

Abstract

mark. Selective expansion of fibroblast subpopulations from pulmonary artery adventitia in response to hypoxia. Am J Physiol Lung Cell Mol Physiol 282: L976-L986, 2002; 10.1152/ajplung.00382.2001.-Proliferation of fibroblasts contributes to the adventitial thickening observed during the development of hypoxia-induced pulmonary hypertension. However, whether all or only specific subpopulations of fibroblasts proliferate during this process is unknown. Because lung, skin, and gingiva contain multiple fibroblast subpopulations, we hypothesized that the pulmonary artery (PA) adventitia of neonatal calves is composed of multiple fibroblast subpopulations and that only selective subpopulations expand under chronic hypoxic conditions. Fibroblast subpopulations were isolated from PA adventitia of control calves using limited dilution cloning techniques. These subpopulations exhibited marked differences in morphology, actin expression, and serum-stimulated growth. Only select fibroblast subpopulations demonstrated the ability to proliferate in response to hypoxia. Fibroblast subpopulations were similarly isolated from calves exposed to hypoxia (14 days). With regard to morphology, actin expression, and serumstimulated growth of subpopulations, there were no obvious differences in fibroblast subpopulations between the hypoxic and the control calves. However, the number of fibroblast subpopulations with about a twofold increase in hypoxiainduced DNA synthesis was significantly greater in the hypoxic calves (26%) compared with control calves (10%). We conclude that the bovine PA adventitia comprises numerous phenotypically and biochemically distinct fibroblast subpopulations and that select subpopulations expand in response to chronic hypoxia. fibrosis; vascular disease; vascular remodeling; fibroblast growth; hypoxia-induced proliferation HYPOXIA-INDUCED pulmonary hypertension complicates the clinical course of many important lung diseases in both children and adults (23,42,46). The pulmonary hypertension and accompanying structural remodeling is particularly severe in infants, and often the earliest and most dramatic structural changes are found in the adventitial compartment of the vessel wall (31,46). In animal models, the resident adventitial fibroblasts have been shown to exhibit early and sustained increases in proliferation and matrix protein synthesis under hypoxic conditions, and these changes have been associated with luminal narrowing and a progressive decrease in the ability of the vessel wall to respond to vasodilating stimuli (3,23,30,45,46). Furthermore, in response to different stimuli, adventitial fibroblasts isolated from hypoxia-induced pulmonary hypertensive neonatal calves demonstrate greater growth capabilities than those from control animals (8), which could be the result of a generalized or polyclonal activation of resident adventitial fibroblasts. Alternatively, it could be the result of the presence of increased numbers of specific fibroblast subpopulations with distinct growth characteristics a...

Hypoxia-Induced Pulmonary Vascular Remodeling

“…168,169 It should be stressed that the arterial adventitia, like the lung interstitium, is composed of heterogeneous fibroblast populations and that only specific subsets of fibroblasts appear capable of proliferating in response to hypoxia. 20,170 Experimental evidence suggests that a selective expansion of these "hypoxia-sensitive" fibroblast subpopulations accounts for the marked accumulation of fibroblasts in the adventitia of chronically hypoxic animals, also consistent with observations that fibrogenic foci in the lung are comprised of selective fibroblast populations. 20,170 PA adventitial fibroblasts derived from chronically hypoxic animals exhibit heightened growth responses to a number of growth promoting stimuli including hypoxia as well as alterations of proliferation associated signaling pathways, compared with fibroblasts derived from normoxic animals.…”

Critical Genomic Networks and Vasoreactive Variants in Idiopathic Pulmonary Arterial Hypertension

“…Further strengthening this association are Wnt variants present in multiple patients. Finally, to strengthen the gene variant findings, we tested the hypothesis that this pathway was of relevance to the IPAH (37,38). Using human lung fibroblast lines, we found evidence of altered expression of Wnt pathway-modulating genes; borderline increased expression of Wisp1, a Wnt target regulating proliferation; and significantly increased Wnt activity in response to stimulation by LiCl.…”

“…Fibroblasts have previously been shown to be important in PAH, are from a tissue of relevance in PAH, and can be isolated from patients with IPAH (37,38). We first tested the hypothesis that GVs in Wnt genes may result in altered expression of Wnt genes.…”

Endothelin-A Receptor Blockade Prevents and Partially Reverses Neonatal Hypoxic Pulmonary Vascular Remodeling

“…There is evidence that hypoxia leads to proliferation of specific subpopulations of smooth muscle cells (33) and adventitial fibroblasts (34) in the newborn calf model. The precise mechanisms responsible for the increased thickness of the media with hypoxia remain to be investigated in the mouse model.…”