This document discusses angiogenesis pathways. It begins by introducing angiogenesis and its role in tumor growth. It then provides an overview of angiogenesis, defining it as the formation of new blood vessels from pre-existing vessels in response to various stimuli. This enhances tumor survival and progression as tumors require new blood vessels to obtain oxygen and nutrients. The document then discusses several signaling pathways involved in angiogenesis, including the roles of ROS, calcium homeostasis, HIF1α, and VEGFR2. It concludes by discussing therapeutic angiogenesis and the need to understand molecular mechanisms of angiogenesis and arteriogenesis to treat tissue hypoxia.

1. Angiogenesis pathways
Dr. P. Suganya
Assistant Professor
Sri Kaliswari College, (Autonomous)
Sivakasi

3. Introduction
Angiogenesis plays a central role in tumor
growth and progression, and its implications
have been extensively investigated and
described in the literature for various
cancers. In the early 1970s, Folkman J was the
first to develop the concept of angiogenesis-
dependent tumor growth and postulated that
the specific blocking of blood flow to the
tumor should be a promising strategy for
cancer treatment.

4. Overview of Angiogenesis
 Angiogenesis is defined as the process by which new blood
vessels
 vessels are formed from the pre-existing blood vessels in
response to numerous mechanical, chemical, and inflammatory
stimuli,
 enhancing tumor survival and progression. Tumor growth and
metastasis depend on angiogenesis and lymph angiogenesis.
 Angiogenesis is an important factor in the progression of cancer,
as tumor cells are dependent on neovascularization for oxygen
and nutrients to sustain their growth. Angiogenesis is regulated
through the balance of pro-angiogenic and anti-angiogenic
factors, and these pro-angiogenic factors can be released by a
variety of cells,
 including endothelial cells, monocytes, and tumor cells. During
tumor growth,

5.  excessive release of angiogenic cytokines
and growth factors induces an “angiogenic
switch” which stimulates the quiescent, non-
proliferating, nearby endothelial cells to
grow and promote tumor progression.

6.  Angiogenesis is a complex developmental process involving
basement membrane degradation, endothelial cell
proliferation, migration, and tube formation.
 Angiogenesis plays a central role in normal development and
wound healing and in the etiology of many diseases, such as
psoriasis, diabetic retinopathy, and cancer.
 Since angiogenesis plays an essential role in tumor growth and
invasion, anti-angiogenesis has been pursued for over 20 years
as a route to novel cancer therapies.
 Many anti-angiogenic therapies have now described that
inhibits not only tumor growth but also cancer cell
dissemination.

7. Process of Angiogenesis Signaling Pathways
The cross-talk between ROS and Ca2+ homeostasis might be
important during angiogenesis. It has been shown that, in
response to nitric oxide, ROS can induce the activation of
Ca2+ channels by glutathionylation. The activation of Nox4 ROS
production in response to VEGF seems to be required. Nox2 and
eNOS would participate in such activation downstream of Nox4.
Eventually, this determines the entry of Ca2+ into the endoplasmic
reticulum through Ca2+ channels and into the cytoplasm through
plasma membrane-associated channels.

8. ROS can influence VEGF signaling and angiogenesis through the
regulation of transcription. It has long been known that exogenous
H2O2 can stimulate the expression or the activity of transcription
factors required for angiogenesis, such as Ets-1, NF-kB, and STAT-
3. Moreover, there are a number of important genes required for
angiogenesis whose expression is ROS-dependent, such as
monocyte chemoattractant protein-1 (MCP-1), vascular cell
adhesion molecule 1 (VCAM-1), and matrix metalloproteinases
(MMPs).

9. The transcription factor HIF1α displays a prominent position in
the regulation of hypoxia-induced angiogenesis. The
stabilization of HIF1α under hypoxia drives the expression of
VEGF, angiopoietin, erythropoietin, and SDF-1. All of these
cytokines have angiogenic properties. There are two different
phases of HIF1α hypoxic stabilization. In the early stage, HIF1α
stabilization depends on mitochondrial ROS production, and on
VEGF production; then, VEGF stimulates the production of ROS
through NADPH oxidases, which reinforces HIF1α stabilization.
Interestingly, HIF1α also controls Nox4 promoter activity.

10. VEGFR2 activation begins by receptor dimerization and
transphosphorylation, and then several signaling cascades are
activated downstream, such as Ras/p38 MAPK (mitogen-
activated protein kinase), PI3K/AKT, PLCγ/DAG/PKC/MEK/ERK.
PLCγ can mediate calcium release which is induced by IP3.
Within those pathways, Rac is a key downstream target/effector
of PI3K and can also regulate ADPH oxidase (Nox). It is
important to note that VEGFR2 can be directly modified by ROS,
through the formation of an inactivating intramolecular disulfide
bridge. This could be a feed-forward negative regulation system
important for signal termination.

11. Therapy of Angiogenesis
For therapeutic angiogenesis, it is essential to understand
molecular mechanisms of angiogenesis and arteriogenesis in
relation to tissue hypoxia. While angiogenesis refers to the
process of growing new blood vessels, arteriogenesis involves
remodeling of existing arterial vessels. Under tissue ischemia,
angiogenesis and arteriogenesis simultaneously take place
and both processes are essential for the establishment of
functional collateral networks. Regulation of angiogenesis and
arteriogenesis may involve a distinct set of vascular
modulators that jointly accomplish the complex processes of
angiogenic and vascular remodeling.