3.11 PAH and EPCs
The usual hypothesis is that a low level of EPCs is one of the conditions for the occurrence of PAH. In research regarding congenital heart disease (CHD) that caused PAH in childhood, severe PAH patients (mean pulmonary arterial pressure > 25 mmHg) show a significantly lower EPC level as compared to non-PAH patients. This phenomenon shows that low level of EPCs is strongly correlated with PAH. However, this relationship was not apparent for patients with mild PAH, indicating that a decreased level of EPC is not the only pathogenesis, or the EPC level will not be significantly decreased in the early stage of PAH(H. X. Sun et al., 2019). The same result was also obtained for adult patients, and in a comparison of COPD and COPD-PAH patients, the latter group showed a significantly lower EPC level as compared to COPD patients(P. Liu et al., 2016). A different conclusion was reached by a group of English scientists, who found that the level of EPCs was increased in idiopathic pulmonary arterial hypertension (iPAH) patients with bone morphogenetic protein type II receptor (BMPR2) mutation (which is a classical mutation that results in the development of iPAH).
In order to explain this aberration, a comparison was made between the EPC screening conditions in different studies (Table 1). We found that almost all scientists use different testing conditions, and the different markers may correspond to different cell groups and different cell functions, finally leading to the chaos of conclusions(Toshner et al., 2009). These different definitions of EPCs cause academic disruption that increases the difficulty and cost of discussions and experiments, and eventually leads to the standstill of progress. Despite the existence of contrary opinions, there is a consensus by most scientists that the low level of EPCs is part of an indispensable process that results in the development of PAH. They suggest that in the initial stage of PAH, high levels of cycling EPCs are able to repair the loss of vessels. However, with the progression of disease, the continuous damage exceeds the compensatory ability of EPCs, which finally leads to the reduction of peripheral EPCs and additional destruction of vessel structure. Ultimately, this process causes stiffer and narrower vessels and a higher pulmonary arterial pressure.
Under this vicious cycle, the symptoms of PAH become increasingly severe and finally lead to death(Toshner et al., 2009). EPCs exist in numerous ways to prevent the development and reverse existing PAH, and mainly include direct incorporation to sites of impaired vessels for repair, playing supportive roles in cellular repair, inhibiting the transfer of ECs, and participating in immunosuppression functions and secretion functions such as secretome, exosome and extracellular vehicles (EVs)(Bayraktutan, 2019; Bianconi et al., 2018; Wei et al., 2013).