Nevertheless, the normal function of eNOS can be impaired by a deficiency of eNOS co-factors, such as tetrahydrobiopterin (BH4), shortage of eNOS substrate L-arginine, disruption of the dimeric eNOS complex, impaired expression or function of eNOS activity regulators, including calcium/calmodulin, caveolin, and HSP90, and the increased production of eNOS endogenous inhibitor, asymmetric dimethylarginine (ADMA), all of which are implicated in PAH. Here, NOS3 is linked to pulmonary arterial hypertension.