Spatio-temporal diversity of apoptosis within the vascular wall in pulmonary arterial hypertension: heterogeneous BMP signaling may have therapeutic implications

ED Michelakis - Circulation research, 2006 - Am Heart Assoc
Circulation research, 2006Am Heart Assoc
Although pulmonary arterial hypertension (PAH) was originally thought to be a disease of
increased pulmonary arterial (PA) tone, we now know that vasoconstriction is important only
in a minority of patients. 1 PAH is characterized by increased proliferation of PA endothelial
cells (PAECs) and PA smooth muscle cells (PASMCs), leading to narrowing or even
obliteration of the PA lumen, increased pulmonary vascular resistance (PVR), right
ventricular failure and premature death. 1 Voelkel and Tuder suggested that the proliferative …
Although pulmonary arterial hypertension (PAH) was originally thought to be a disease of increased pulmonary arterial (PA) tone, we now know that vasoconstriction is important only in a minority of patients. 1 PAH is characterized by increased proliferation of PA endothelial cells (PAECs) and PA smooth muscle cells (PASMCs), leading to narrowing or even obliteration of the PA lumen, increased pulmonary vascular resistance (PVR), right ventricular failure and premature death. 1 Voelkel and Tuder suggested that the proliferative remodeling in the PAs resembles cancer. 2 Several features, in addition to excessive proliferation, make this hypothesis attractive. For example, as in cancer, the development of PAH appears to result from a “multiple-hit” mechanism, where environmental factors (virus, inflammation, anorexigens, shunt-induced shear stress, etc) interact with a genetic predisposition (loss-of-function mutations in the bone morphogenetic protein receptor II, BMPR-II) culminating in disease. 1 That PAH is characterized by a cancer-like apoptosis resistance is supported by recent reports that proapoptotic therapies can reverse PAH, similarly to cancer, where proapoptotic chemotherapies are the mainstay of treatment. Several experimental PAH treatments (including dichloroacetate, 3 simvastatin, 4 sildenafil, 5 imatinib, 6 anti-survivin, 7 and K channel replacement gene therapies8) induce apoptosis of PASMCs, leading to reversal of vascular remodeling and PAH. In sharp contrast, strategies designed to promote survival and inhibit apoptosis of PAECs (cell-based gene transfer of angiopoietin-19 or eNOS, 10 caspase inhibitors11) also improve PAH, particularly at early stages. These apparently conflicting reports can be rationalized by the hypothesis that vascular apoptosis is regulated in a compartment-specific manner.
The role of apoptosis in the pathogenesis of PAH is also supported by the discovery that mutations in BMPR-II predispose patients to familial PAH. 12 Like most mediators involved in embryological development, BMPs are important regulators of apoptosis. It was initially assumed that loss-offunction BMPR-II mutations would suppress apoptosis and increase proliferation in the PA wall, perhaps fully explaining the vascular remodeling in PAH. However it is now recognized that although most familial PAH patients carry mutations, they are found in only 10% of patients with sporadic idiopathic PAH (iPAH) and their presence confers only a 15% to 20% chance of PAH in a carrier’s lifetime. 12 Nevertheless, this discovery offered new insights into the biology of PAH.
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