A current concept of PH pathogenesis
A current concept of PH pathogenesis describes a phenotypic switch of PASMC from a contractile (differentiated) to a synthetic/proliferative (de-differentiated) state. The latter is considered to drive medial thickening and thus vascular remodeling in PH . According to this concept, the Conessine of contractile markers (α-SMA, myocardin) declines whereas cell proliferation and migration as well as production of ECM proteins (FN, collagens, OPN) increase in de-differentiated PASMC [4,18]. Although LRP1 did not promote PASMC migration, it decreased the expression of α-SMA and myocardin and elevated the production of ECM proteins as well as PASMC proliferation. These findings indicate that LRP1 does not act alone, but in concert with other factors, to facilitate the de-differentiation of PASMC. Several molecules/conditions were found to contribute to the transition of PASMC from a contractile to a synthetic state, among others PDGF-BB , STIM, Orai2 , α-enolase , and hypoxia  thus implying that a number of biological and environmental factors accompany the process of SMC de-differentiation. Noteworthy, the contractile and the synthetic phenotype of SMC represent two extremes of continuum. Between these two extremes, a high number of intermediate phenotypes, which are characterized by the selective acquisition of the features of both SMC states, exist. Thus, the increased LRP1 expression in PASMC and the cellular consequences of thereof may represent just one of the stages of the de-differentiation process. Interestingly, in PASMC isolated from IPAH lungs, LRP1 depletion did suppress cell proliferation and Col I protein expression, however, it did not affect the expression of the contractile phenotype markers. This suggests that, although LRP1 may promote the phenotypic switch of PASMC in PH, other factors are, in addition, needed to fully restore the differentiated state of PASMC .
Growth promoting activities of LRP1 in donor as well as IPAH PASMC were strongly dependent on the expression of β1-integrin. Altered levels of various integrins are considered to drive vascular remodeling in experimental models of PH by disturbing SMC-ECM communication . For example, αvβ3-integrin was found to mediate osteoprotegerin-triggered PASMC proliferation and hence vascular remodeling of pulmonary vessel in mice exposed to hypoxia and SU5416 . β3-integrin was also critical for growth, migration and ECM production of PASMC exposed to connective tissue growth factor . We show for the first time the dependency of β1-integrin expression on LRP1 in PASMC and the association between β1-integrin abundance and the PASMC replication rate. These results are corroborated by the increased levels of LRP1 and β1-integrin in highly proliferating IPAH PASMC. Strikingly, previous studies highlighted the augmented α5β1-integrin levels in less differentiated SMC following injury and the inverse relationship between α5β1-integrin and α-SMA expression in SMC . These findings are in line with our observation of the elevated α-SMA levels in PASMC characterized by low LRP1 abundance and hence decreased expression of β1-integrin. The direct association between β1-integrin expression and phenotypic transition of PASMC requires, however, further exploration.
Following injury, LRP1 tries to orchestrate many processes that are crucial for repairing damaged vessels. By controlling the expression of integrins, MMPs, and ECM components, it ensures proper communication of the SMC within an ever changing environment. Whether the elevated expression of LRP1 in PASMC isolated from IPAH lungs tries to compensate or rather propagates vascular damage has to be answered in future in vivo studies.
Introduction Retinopathy is one of the most devastating complications of diabetes, and the molecular mechanism of this complex blinding disease remains obscure. Recent research has led to a greater appreciation of how mitochondrial dysfunction could contribute to diabetic complications including neuropathy, nephropathy and retinopathy [, , , , ]. Retinal mitochondria are damaged in diabetes, they become swollen and their membranes leak cytochrome c in the cytosol, which accelerates the apoptotic process. Furthermore, mitochondria copy numbers are decreased, and their DNA (mtDNA) is damaged. Due to impaired transcription of mtDNA-encoded proteins, the electron transport chain is compromised, and the vicious cycle of free radicals continues to self-propagate [, , ].