It is also of interest that the complex vascular lesions that characterize the SU5416/hypoxia rat model of severe PH23 also have diminished or absent expression of caveolin 1 and 2. Further, it appears that in the lung there is a co-expression of caveolin1 and HO-1 protein, similar to that described in mouse mesangial cells.
HO-1 has antioxidant functions,41 and enhancement of endogenous HO-1 prevents hypoxia-induced PH.27 Thus, loss of expression of HO-1 in the complex pulmonary hypertensive lesions could contribute to an oxidant stress milieu in the lungs from patients with severe PH. Not only might HO-1 and caveolin 1 coexist in caveolae, but there may also be coexistence of peroxisome proliferator-activated receptor (PPAR)-7 and caveolin 1, since it has been shown that PPAR-7 participates in the regulation of caveolin gene expression in cancer cells. However, VEGF receptor 2 (KDR) activity is regulated by caveolin 1,>45 and incubation of endothelial cells with VEGF leads to a marked down-regulation of caveolin 1. http://birthcontroltab.com/
In this context, we have reported marked overexpression of both VEGF and VEGF receptor 2 proteins in the plexiform lesions31 as well as loss of expression of PPAR-7 protein,47 and we can now characterize these vascular lesion cells as apoptosis resistant and angiogenic. We suggest that both the overexpression of VEGF ligand and the loss of PPAR-7 protein may contribute to the decrease in cellular caveolin expression and that the decreased caveolin expression may, in turn, contribute to enhanced VEGF receptor-induced signaling and endothelial cell proliferation18 (Fig 9). Whether VEGF ligand and PPAR-7 can also determine HO-1 expression is unknown.
Lastly, there is emerging evidence that caveolin expression is also tied to the fate of vascular smooth-muscle cells (VSMCs); caveolin expression is decreased in secretory VSMC phenotypes as compared to contractile phenotypes or proliferating VSMCs., Loss or decreased expression of the caveolins in the pulmonary hypertensive plexiform lesion smooth-mus-cle cells and the smooth-muscle cells of the hypertrophied pulmonary arteries may be a marker of a proliferating, apoptosis-resistant VSMC phenotype. It remains unclear, however, whether loss of caveolin expression precedes cell proliferation. We propose that the multiple phenotypical alterations of the plexiform lesion cells are part of a quasimalignant cell growth program, ie, growth-inhibiting genes are being switched off and growth-promoting genes are being turned on.
Figure 9. Schematic illustrating the possible relationships between VEGF, PPAR-7, caveolin, and angiogenesis. VEGFRII = VEGF receptor 2.