Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 480

9.5.3.7 BMPRs

Bone morphogenetic proteins link to BMPR1 and BMPR2, thereby causing phos-
phorylation of BMPR-specific SMADs (SMAD1, SMAD5, and SMAD8). Blood
flow provokes BMP4 synthesis in endothelial cells.
Endothelial cells exposed to time-dependent shear stress have higher turnover
(and proliferation) rate than those bearing steady shear stress. The SMAD proteins
can modulate the cell cycle, which is controlled by cyclin-dependent protein kinases
coupled to their regulatory subunits cyclins and inhibitors CKI1a and CKI1b.
In endothelial cells, SMAD1 and SMAD5 can be activated from BMPR in the
absence of BMP ligands to promote cell proliferation, unlike BMP4-dependent
ICAM1 expression by nuclear factor-

B in the context of inflammation to support
monocyte adhesion to the endothelium [ 889 ]. Time-dependent shear stress actually
causes a sustained activation of SMAD1 and SMAD5 and subsequently of TOR
and S6K (or P70 RSK) kinases, thereby upregulating cyclin-A and downregulating
CKI1a and CKI1b [ 889 ]. Shear-mediated activation of TOR and S6K is modulated
by the interplay between AMPK inhibitor and PKB activator.

κ

9.5.3.8 Neurotrophin Tyr Kinase Receptors

Neurotrophins, such as nerve growth factor, brain-derived neurotrophic factor
(BDNF), and neurotrophin-3 and their high-affinity neurotrophin Tyr kinase re-
ceptors (NTRK2-NTRK3) 34 and low-affinity nerve growth factor receptor (NGFR,
or TNFRSF16) 35 localize to pulmonary vasculature and airways in humans. Both
ligands and receptor are produced in the same cell type to create auto-, juxta-, or
paracrine effects. In addition, endothelial cells of the systemic circulation produce
NTRK receptors. Moreover, BDNF circulates in blood (15-30 ng/ml).
Neurotrophins rapidly trigger (6-8 mn) nitric oxide production in pulmonary
endothelial cells [ 890 ]. Neurotrophins BDNF and NT3 act predominantly via
high-affinity NTRK2 and NTRK3 receptors, respectively, with partial involve-
ment of low-affinity TNFRSF16 receptor. Upon NTRK autophosphorylation, both
BDNF and NT3 increase phosphorylation of PKB that, in turn, phosphorylates
NOS3 kinase. As, in smooth myocytes, neurotrophins increase intracellular Ca 2 +

34 Nerve growth factor preferentially binds to NTRK1, brain-derived neurotrophic factor to
NTRK2, and neurotrophin-3 to NTRK3. In lungs, neurotrophins and their receptors reside in
nerves, immunocytes, epithelial and smooth muscle cells, fibroblasts, and pulmonary vascular
cells. In human airway smooth myocytes, BDNF and neurotrophin-3 can rapidly increase and
decrease intracellular Ca 2 + level, respectively. Both NGF and BDNF are involved in cardiovascular
development and ischemia [ 890 ].
35 Receptor TNFRSF16 is expressed in both endothelial and smooth muscle cells in mouse
pulmonary arteries.