Instead, the left heart fails to pump blood efficiently, leading to pooling of blood in the lungs and back pressure within the pulmonary system. This causes pulmonary edema and pleural effusions. In the absence of pulmonary blood vessel narrowing, the increased back pressure is described as isolated post-capillary pulmonary hypertension (older terms include passive or proportionate pulmonary hypertension or pulmonary venous hypertension). However, in some patients, the raised pressure in the pulmonary vessels triggers a superimposed component of vessel narrowing, which further increases the workload of the right side of the heart. This is referred to as post-capillary pulmonary hypertension with a pre-capillary component or combined post-capillary and pre-capillary pulmonary hypertension (older terms include reactive or out-of-proportion pulmonary hypertension).In pulmonary hypertension due to lung diseases and/or hypoxia (WHO Group III), low levels of oxygen in the alveoli (due to respiratory disease or living at high altitude) cause constriction of the pulmonary arteries. This phenomenon is called hypoxic pulmonary vasoconstriction and it is initially a protective response designed to stop too much blood flowing to areas of the lung that are damaged and do not contain oxygen. When the alveolar hypoxia is widespread and prolonged, this hypoxia-mediated vasoconstriction occurs across a large portion of the pulmonary vascular bed and leads to an increase in pulmonary arterial pressure, with thickening of the pulmonary vessel walls contributing to the development of sustained pulmonary hypertension.
Prolonged hypoxia also induces the transcription factor HIF1A, which directly activates downstream growth factor signaling that causes irreversible proliferation and remodeling of pulmonary arterial endothelial cells, leading to chronic pulmonary arterial hypertension.In CTEPH (WHO Group IV), the initiating event is thought to be blockage or narrowing of the pulmonary blood vessels with unresolved blood clots; these clots can lead to increased pressure and shear stress in the rest of the pulmonary circulation, precipitating structural changes in the vessel walls (remodeling) similar to those observed in other types of severe pulmonary hypertension. This combination of vessel occlusion and vascular remodeling once again increases the resistance to blood flow and so the pressure within the system rises. Molecular pathology
The molecular mechanism of pulmonary arterial hypertension (PAH) is not known yet, but it is believed that the endothelial dysfunction results in a decrease in the synthesis of endothelium-derived vasodilators such as nitric oxide and prostacyclin. Moreover, there is a stimulation of the synthesis of vasoconstrictors such as thromboxane and vascular endothelial growth factor (VEGF). These result in a severe vasoconstriction and vascular smooth muscle  and adventitial hypertrophy characteristic of patients with PAH. Nitric oxide-soluble guanylate cyclase pathway
In normal conditions, the vascular endothelial nitric oxide synthase produces nitric oxide from L-arginine in the presence of oxygen.This nitric oxide diffuses into neighboring cells (including vascular smooth muscle cells and platelets), where it increases the activity of the enzyme soluble guanylate cyclase, leading to increased formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP).