16 Mechanism and Consequence of Vasomotion
265
of lymph-vessels [58]. This hypothesis could be tested when the membrane proteins
responsible for the Cl
− conductance were known. It turned out that two proteins
were necessary for the Ca
2+ -activated, cGMP-dependent Cl
− conductance. One is a
protein called TMEM16A [7] and the other protein is called bestrophin [40]. If the
Ca
2+ -activated and cGMP-dependent Cl
− conductance is important for vasomotion,
the latter should be disturbed if TMEM16A or bestrophin is knocked out. Using gene
targeting approaches we performed knock-down of these two gene products in the
smooth muscle cells and showed that this is associated with gross disturbance of
vasomotion [5, 7]. This confirmed a model for vasomotion where a mixed cytosolic
and membrane oscillator result in entrainment of oscillating smooth muscle cells to
produce vasomotion. The basis for this model is a loop where Ca
2+ released from
the sarcoplasmic reticulum activates a Cl
− conductance in the cell membrane. This
leads to membrane depolarization, consequent influx of Ca
2+ , and refilling of the
sarcoplasmic reticulum. A delay in this loop sets up the oscillation and the loop
involves a reciprocal interaction between release of Ca
2+ from the sarcoplasmic
reticulum and the membrane potential.
It is important to emphasize that there is experimental evidence for other mechanisms leading to vasomotion as well. Some of these are not dependent on release
of Ca
2+ from the intracellular Ca
2+ stores and solely depend on a membrane oscillator. In other situations, the endothelial cells seem to prevent vasomotion rather than
promote it, as it was the case in the example discussed above.
16.4 Microvascular Networks
The small arteries connect to form networks. These are highly branched, space
filling structures, permeating the tissue. Successive branching ultimately places the
primary exchange vessels, the capillaries, within close proximity of any tissue cell.
As described mathematically already long ago by Krogh [32] the remaining distance
for nutrients and waste products can thereby be efficiently bridged by diffusion.
Microvascular networks are constantly adapting to long-term changes in structure
and demand of the surrounding tissue. As e.g. skeletal muscle tissue increases in size
under physical training, the microvascular supply network must change accordingly.
This process, characterized by sprouting of numerous new vessels from existing ones
and subsequent pruning and remodeling to form a mature network [44], (reviewed
in [35]), encompasses substantial variation which is reflected in the final network
structure. Hence, microvascular networks are inherently heterogeneous structures
[12]. Different flow routes through the network therefore tend to have different
hydraulic resistances. At normal perfusion levels, this heterogeneity will not compromise delivery of oxygen and nutrients to any tissue region, since resistance vessels
upstream of the capillary bed can actively change diameter to compensate for inadequate perfusion of a given area. If e.g., perfusion pressure drops or local tissue
metabolism increases, resistance vessels dilate to ensure adequate perfusion of their
local region. In particular, the dependence of artery diameter on transmural pressure,
265
of lymph-vessels [58]. This hypothesis could be tested when the membrane proteins
responsible for the Cl
− conductance were known. It turned out that two proteins
were necessary for the Ca
2+ -activated, cGMP-dependent Cl
− conductance. One is a
protein called TMEM16A [7] and the other protein is called bestrophin [40]. If the
Ca
2+ -activated and cGMP-dependent Cl
− conductance is important for vasomotion,
the latter should be disturbed if TMEM16A or bestrophin is knocked out. Using gene
targeting approaches we performed knock-down of these two gene products in the
smooth muscle cells and showed that this is associated with gross disturbance of
vasomotion [5, 7]. This confirmed a model for vasomotion where a mixed cytosolic
and membrane oscillator result in entrainment of oscillating smooth muscle cells to
produce vasomotion. The basis for this model is a loop where Ca
2+ released from
the sarcoplasmic reticulum activates a Cl
− conductance in the cell membrane. This
leads to membrane depolarization, consequent influx of Ca
2+ , and refilling of the
sarcoplasmic reticulum. A delay in this loop sets up the oscillation and the loop
involves a reciprocal interaction between release of Ca
2+ from the sarcoplasmic
reticulum and the membrane potential.
It is important to emphasize that there is experimental evidence for other mechanisms leading to vasomotion as well. Some of these are not dependent on release
of Ca
2+ from the intracellular Ca
2+ stores and solely depend on a membrane oscillator. In other situations, the endothelial cells seem to prevent vasomotion rather than
promote it, as it was the case in the example discussed above.
16.4 Microvascular Networks
The small arteries connect to form networks. These are highly branched, space
filling structures, permeating the tissue. Successive branching ultimately places the
primary exchange vessels, the capillaries, within close proximity of any tissue cell.
As described mathematically already long ago by Krogh [32] the remaining distance
for nutrients and waste products can thereby be efficiently bridged by diffusion.
Microvascular networks are constantly adapting to long-term changes in structure
and demand of the surrounding tissue. As e.g. skeletal muscle tissue increases in size
under physical training, the microvascular supply network must change accordingly.
This process, characterized by sprouting of numerous new vessels from existing ones
and subsequent pruning and remodeling to form a mature network [44], (reviewed
in [35]), encompasses substantial variation which is reflected in the final network
structure. Hence, microvascular networks are inherently heterogeneous structures
[12]. Different flow routes through the network therefore tend to have different
hydraulic resistances. At normal perfusion levels, this heterogeneity will not compromise delivery of oxygen and nutrients to any tissue region, since resistance vessels
upstream of the capillary bed can actively change diameter to compensate for inadequate perfusion of a given area. If e.g., perfusion pressure drops or local tissue
metabolism increases, resistance vessels dilate to ensure adequate perfusion of their
local region. In particular, the dependence of artery diameter on transmural pressure,