Apoptotic ECs appear early but are progressively replaced by apoptosis-resistant and hyperproliferative ECs, which ultimately form disorganized neointimal lesions (2–4). Early events during PAH pathogenesis include the onset of vascular wall stiffening and inflammatory responses, including infiltration by diverse inflammatory cell types. Genetic mutations or combined insults lead to insufficient BMPRII levels and SMAD1/5/8 signaling in multiple vascular cell types. Laminar blood flow patterns promote BMPRII-pathway signaling in ECs and maintain vascular quiescence (1). Under normal conditions, the pulmonary distal arterioles comprise an intimal monolayer of ECs and are largely devoid of a medial layer with SMCs. Cellular, molecular, and biomechanical progression of PAH in the pulmonary arterial wall. Research into PAH disease mechanisms has also highlighted the critical roles of other signal transduction pathways, especially those of the transforming growth factor-β (TGF-β) superfamily, which interact with inflammatory processes and biomechanical forces to regulate EC and SMC proliferation.įigure 1. Studies on the platelet-derived growth factor receptor pathway, which is strongly upregulated in the distal pulmonary arteries of PAH patients and contributes to over-proliferation ( 4), have suggested that reversal of pathology is clinically achievable ( 5, 6)-although safer alternative strategies are desirable ( 7). Accordingly, targeting the proliferation of SMCs and ECs to treat PAH has been the subject of extensive efforts over the last two decades. Endothelial cells (ECs) also over-proliferate and in later stages of disease can form neointimal lesions that obstruct distal arterioles ( 3). Smooth muscle cells (SMCs) over-proliferate and thereby thicken vessel walls and cause vascular muscularization, including around the distal arterioles where SMCs are not normally found. Multiple cell types of the pulmonary arterial wall contribute to vascular remodeling in PAH ( Figure 1) ( 2). Loss of luminal space in turn increases pulmonary vascular resistance and pulmonary arterial pressure, leading to strain on the right cardiac ventricle and ultimately to heart failure ( 1).
The primary pathology is thought to originate in the small distal arterioles, in which uncontrolled proliferation of vascular cells results in narrowing and occlusion of the vascular lumen. In pulmonary arterial hypertension (PAH), pathologic vascular remodeling distorts the gross- and micro-scale structure of the pulmonary arterial vasculature, severely disrupting blood flow patterns throughout the cardiopulmonary circulation. TGF-β Superfamily Dysregulation Is a Critical Component of PAH
These strategies could potentially reverse pulmonary arterial remodeling in PAH by targeting causative mechanisms and therefore hold significant promise for the PAH patient population. We review the TGF-β superfamily mechanisms underlying PAH pathogenesis, superfamily interactions with inflammation and mechanobiological forces, and therapeutic strategies under development that aim to restore SMAD signaling balance in the diseased pulmonary arterial vessels. Imbalanced signaling by the transforming growth factor-β (TGF-β) superfamily contributes extensively to dysregulated vascular cell proliferation in PAH, with overactive pro-proliferative SMAD2/3 signaling occurring alongside deficient anti-proliferative SMAD1/5/8 signaling. Available treatments improve physical activity and slow disease progression, but they act primarily as vasodilators and have limited effects on the biological cause of the disease-the uncontrolled proliferation of vascular endothelial and smooth muscle cells. Pulmonary arterial hypertension (PAH) is a rare disease characterized by high blood pressure in the pulmonary circulation driven by pathological remodeling of distal pulmonary arteries, leading typically to death by right ventricular failure. Discovery Group, Acceleron Pharma (a wholly-owned subsidiary of Merck & Co., Inc.), Cambridge, MA, United States.
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