17
new hypothesis which states that Cdc42 and MT1-MMP are interdependent signaling molecules that control vascular morphogenic events specifically in a 3D matrix
environment.
1.3.10 Critical Role for MMPs in the Molecular Control
of Vascular Tube Regression Responses in 3D Collagen
Matrices
A critically important direction of research is to understand how blood vessels
regress under physiologic and pathophysiologic situations. Physiologic regression
occurs with hyaloid vessels in the developing eye, in both the endometrium and
ovaries during the menstrual cycle, and during vascular remodeling events in development [33]. Pathophysiologic regression characteristically occurs during wound
repair and during disease processes such as hypertension and diabetes where vessel
densities can decrease particularly in the distal limbs. Also, there have been considerable efforts to induce vascular tube regression responses, in the context of the
tumor vasculature by disrupting VEGF and PDGF signaling [15]. An important
point here is that it is critical to understand how vascular regression is controlled at
the molecular level, in much the same way that the studies described earlier have
been performed to determine how blood vessels form.
A variety of studies have identified MMPs that regulate vascular tube regression
events [32, 86, 109]. A number of years ago, we identified the secreted MMPs
MMP-1 and MMP-10 as being involved in vascular tube regression responses
in vitro [32, 33, 35, 86]. We showed that these enzymes were secreted as proenzymes and that they need to be activated by serine proteases, such as plasminogen/
plasmin or plasma kallikrein, in order to cause vascular tube collapse and regression
[86]. Disruption of their activity by TIMP-1 (which blocks both MMP-1 and MMP10) or blockade of serine protease activity leads to inhibition of the MMP-1- and
MMP-10-dependent regression response. Other studies using the aortic ring model
reached similar conclusions, with the exception that MT1-MMP was also found to
be involved in both tube formation as well as regression [4]. We also identified
ADAM-15 as being involved in the vascular regression response in a manner similar
to that of MMP-1 and MMP-10 [87]. Interestingly, siRNA suppression of either
MMP-1 or MMP-10 did not affect tube formation but markedly blocked tube regression, following addition of plasminogen or plasma kallikrein to the serum-free
media system [86]. Also of note, a mouse knockout of histone deacetylase 7
(HDAC7) caused a vascular hemorrhage phenotype in vivo, during vascular development, which leads to embryonic lethality [20]. siRNA suppression of HDAC7
resulted in marked increases in MMP-10 and marked decreases in TIMP-1 expression which lead to the vascular developmental regression phenomenon [20]. Other
work reveals that EC-specific knockout of the chromatin remodeling enzyme,
1 Molecular Control of Capillary Tube Morphogenesis and Maturation Through…
new hypothesis which states that Cdc42 and MT1-MMP are interdependent signaling molecules that control vascular morphogenic events specifically in a 3D matrix
environment.
1.3.10 Critical Role for MMPs in the Molecular Control
of Vascular Tube Regression Responses in 3D Collagen
Matrices
A critically important direction of research is to understand how blood vessels
regress under physiologic and pathophysiologic situations. Physiologic regression
occurs with hyaloid vessels in the developing eye, in both the endometrium and
ovaries during the menstrual cycle, and during vascular remodeling events in development [33]. Pathophysiologic regression characteristically occurs during wound
repair and during disease processes such as hypertension and diabetes where vessel
densities can decrease particularly in the distal limbs. Also, there have been considerable efforts to induce vascular tube regression responses, in the context of the
tumor vasculature by disrupting VEGF and PDGF signaling [15]. An important
point here is that it is critical to understand how vascular regression is controlled at
the molecular level, in much the same way that the studies described earlier have
been performed to determine how blood vessels form.
A variety of studies have identified MMPs that regulate vascular tube regression
events [32, 86, 109]. A number of years ago, we identified the secreted MMPs
MMP-1 and MMP-10 as being involved in vascular tube regression responses
in vitro [32, 33, 35, 86]. We showed that these enzymes were secreted as proenzymes and that they need to be activated by serine proteases, such as plasminogen/
plasmin or plasma kallikrein, in order to cause vascular tube collapse and regression
[86]. Disruption of their activity by TIMP-1 (which blocks both MMP-1 and MMP10) or blockade of serine protease activity leads to inhibition of the MMP-1- and
MMP-10-dependent regression response. Other studies using the aortic ring model
reached similar conclusions, with the exception that MT1-MMP was also found to
be involved in both tube formation as well as regression [4]. We also identified
ADAM-15 as being involved in the vascular regression response in a manner similar
to that of MMP-1 and MMP-10 [87]. Interestingly, siRNA suppression of either
MMP-1 or MMP-10 did not affect tube formation but markedly blocked tube regression, following addition of plasminogen or plasma kallikrein to the serum-free
media system [86]. Also of note, a mouse knockout of histone deacetylase 7
(HDAC7) caused a vascular hemorrhage phenotype in vivo, during vascular development, which leads to embryonic lethality [20]. siRNA suppression of HDAC7
resulted in marked increases in MMP-10 and marked decreases in TIMP-1 expression which lead to the vascular developmental regression phenomenon [20]. Other
work reveals that EC-specific knockout of the chromatin remodeling enzyme,
1 Molecular Control of Capillary Tube Morphogenesis and Maturation Through…