Sandbox/00025

Pathogenesis

Several pathways are implicated in development of vascular remodeling in the pathogenesis of pulmonary hypertension

1. Thrombosis-mediated remodeling

Thrombin plays a key role in mediating vascular remodeling by activating platelet, upregulating angiogenesis-related genes (including tissue factor, basic fibroblast growth factor, and matrix metalloproteinase-2), and transactivating vascular endothelial growth factor by inducing the production of reactive oxygen species and the expression of the hypoxia inducible factor-1 alpha. Upregulation of tissue factor in the vasculature leads to initiation of coagulation cascade and migration and proliferation of smooth muscle cells upon vascular injury. In addition, platelet activation by thrombin results in the release of granules containing subtances that promote mitogenesis and vasoconstriction including VEGF, bFGF, platelet-derived growth factor, and serotonin, which also contribute to increased endothelial cell migration and proliferation.

2. Vasoconstriction-mediated remodeling

Imbalance of vasoactive signals is suggested in the pathogensis of remodeling. Reduced levels of vasodilatory mediators, in particular prostaglandin I2, nitric oxide, and cyclic guanine monophosphate, and elevated levels of vasocontricting molecules such as endothelin 1, thromboxane, and 5-hydroxytryptamine contribute to the alteration in the vascular tone. Downregulation of the voltage-gated potassium channels has also been linked with altered pulmonary vascular tone, dysregulation of cellular homeostasis, and induction of proliferative sequelae in vascular smooth muscle cells.

3. Proliferation-mediated remodeling

Serotonin exerts both vasoconstrictive and mitogenic effects on smooth muscle cells (SMC). Serotonin may bind to 5-hydroxytryptamine 1A and 2B receptors or may enter SMC via serotonin transporter which induces generation of reactive oxygen species, rho kinase, and mitogen-activated protein kinases. This in turn leads to thhe expression of growth factors and proliferation. Bone morphogenetic protein (BMP) is also involved in the SMC proliferation. Upon binding of BMP to the heterodimerized receptors, a group of cytoplasmic proteins known as receptor-mediated Smads are phosphorylated and translocated to the nucleus where they upregulate genes related to anti-proliferation. Serotonin is shown to antagonize the BMP/Smad pathway thus facilitating the proliferation of smooth muscle cells.

4. Inflammation-mediated remodeling

Influx of inflammatory effectors is stimulated by the release of chemokines such as CCL5 and CX3CL1. On the other hand, endothelial cell and smooth muscle cell dysfunction contributes to the release of vasomotor and growth mediators, activation of transcriptional factors, influx of calcium, and mitochondrial dysfunction. The net effect is a shift of balance in favor of proliferation and suppressed apoptosis, leading to remodeling of the pulmonary vasculature.